The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer

Nanna Jørgensen; Gry Persson; Thomas Vauvert F. Hviid

doi:10.3389/fimmu.2019.00911

The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer

Jørgensen, Nanna;Persson, Gry;Hviid, Thomas Vauvert F. 2019-05-08 00:00:00 REVIEW published: 08 May 2019 doi: 10.3389/ﬁmmu.2019.00911 The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer Nanna Jørgensen, Gry Persson and Thomas Vauvert F. Hviid* Department of Clinical Biochemistry, Centre for Immune Regulation and Reproductive Immunology (CIRRI), The ReproHealth Consortium ZUH, Zealand University Hospital, and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Regulatory T cells, a subpopulation of suppressive T cells, are potent mediators of self-tolerance and essential for the suppression of triggered immune responses. The immune modulating capacity of these cells play a major role in both transplantation, autoimmune disease, allergy, cancer and pregnancy. During pregnancy, low numbers of regulatory T cells are associated with pregnancy failure and pregnancy complications such as pre-eclampsia. On the other hand, in cancer, low numbers of immunosuppressive T cells are correlated with better prognosis. Hence, maternal immune tolerance toward the fetus during pregnancy and the escape from host immunosurveillance by cancer seem to be based on similar immunological mechanisms Edited by: being highly dependent on the balance between immune activation and suppression. Djordje Miljkovic, As regulatory T cells hold a crucial role in several biological processes, they may also University of Belgrade, Serbia be promising subjects for therapeutic use. Especially in the ﬁeld of cancer, cell therapy Reviewed by: Carlo Riccardi, and checkpoint inhibitors have demonstrated that immune-based therapies have a University of Perugia, Italy very promising potential in treatment of human malignancies. However, these therapies Katarina Mirjacic Martinovic, Institute of Oncology and Radiology of are often accompanied by adverse autoimmune side effects. Therefore, expanding Serbia, Serbia the knowledge to recognize the complexities of immune regulation pathways shared *Correspondence: across different immunological scenarios is extremely important in order to improve and Thomas Vauvert F. Hviid develop new strategies for immune-based therapy. The intent of this review is to highlight [email protected] the functional characteristics of regulatory T cells in the context of mechanisms of Specialty section: immune regulation in pregnancy and cancer, and how manipulation of these mechanisms This article was submitted to potentially may improve therapeutic options. Immunological Tolerance and Regulation, Keywords: regulatory T cells, immune tolerance, cancer, immunotherapy, pregnancy, preeclampsia, HLA class Ib a section of the journal Frontiers in Immunology Received: 15 November 2018 INTRODUCTION Accepted: 09 April 2019 Published: 08 May 2019 Regulatory T cells (Tregs) constitute a dynamic and diverse T cell population composed of several Citation: subsets distinguished by phenotypic and functional characteristics. With their immunosuppressive Jørgensen N, Persson G and properties, Tregs are central to the maintenance of immune homeostasis. They are implicated Hviid TVF (2019) The Tolerogenic in critical immunoregulatory functions in several physiological conditions such as inﬂammatory Function of Regulatory T Cells in responses, tissue repair, and reproduction. Furthermore, Tregs also play an important role in the Pregnancy and Cancer. pathophysiological immune tolerance induced by tumors (1–4). Hence, selective immunological Front. Immunol. 10:911. doi: 10.3389/ﬁmmu.2019.00911 tolerance is essential during any of these processes, and the mechanisms by which immune Frontiers in Immunology | www.frontiersin.org 1 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer tolerance is sustained by Tregs might be similar. Some of the mechanisms responsible for induction of maternal immune tolerance during pregnancy may be the same as those involved in controlling an inﬂammatory response from not exaggerating beyond control, and furthermore the same mechanisms that may provide a pro-tumorigenic environment which allows cancer development. The role of Tregs is somewhat opposing in relation to a role in protecting the body and preventing disease development. Tregs must allow protective immune responses against pathogens and tumors, but simultaneously prevent inﬂammatory diseases by restraining aberrant responses to self and innocuous antigens with pregnancy as a borderline condition, where Tregs contribute to the establishment of active immune tolerance toward the fetus (Figure 1). The similarities between reproductive biology and cancer development in terms of immunology is not that implausible. During pregnancy, the formation of the placenta involves the invasion of the semi-allogeneic fetal trophoblast cells into the maternal tissue for anchoring and vascular adaptions, such as formation of spiral arteries providing nutritional support for the growing fetus. The maternal immune system has to allow this invasion of partly foreign cells to ensure a successful pregnancy. Thus, cancer cells and cells of the developing placenta both share the capacity to invade normal tissue and create a microenvironment that support immunologic privilege and angiogenesis (Figure 1). The proliferation and migration of cancer cells at a distant site mediated in part by modulation of a tolerogenic immune response in the tumor microenvironment may be compared to the situation in pregnancy, in which the developing placenta invades the uterus and a semi-allogenic fetus escapes rejection from the maternal immune system (5– 7). A prominent hypothesis states that the failure to establish immune tolerance during pregnancy may lead to pregnancy complications or pregnancy loss. However, this may indicate that it should be possible to exploit the same mechanisms responsible for immune regulation during pregnancy in treatment of cancer and to reject cancer cells by immunological mechanisms (5). Finally, it is important to remember that immunomodulation and immunosuppression during pregnancy are physiological FIGURE 1 | Immune mechanisms during pregnancy and cancer development. mechanisms but in cases of cancer they are pathological and in Although immunomodulation during pregnancy is a physiological process and most cases unfavorable. in cases of cancer a pathophysiological process, there are a number of similarities in cellular and molecular mechanisms at the feto-maternal interface The function of Tregs as potent anti-inﬂammatory cells and in the tumor microenvironment. Tumors and fetuses seem to exploit some has led to considerable interest in their therapeutic potential. of the same immunomodulating mechanisms. Formation of the placenta In cancer, there has been much progress within the ﬁeld of during pregnancy involves invasion of fetal trophoblast cells into the maternal immunotherapy within the last decade. Especially, cancer therapy tissue for anchoring and vascular adaptions. In cancer, local invasion into by inhibition of negative immune regulation is already used neighboring tissue is essential for manifestation of malignant growth and the ﬁrst stage in development of secondary tumors or metastases. Furthermore, in the clinic. Manipulation and propagation of Tregs and their several immune cells are present both at the feto-maternal interface and in the therapeutic application is a promising approach in order to reach tumor microenvironment, here with malignant melanoma as an example. There a clinical beneﬁt for aﬀected patients (8–10). is increasing evidence that regulatory T cells play important roles both in As brieﬂy mentioned above, while pregnancy is a physiological cancer and in reproduction. [Illustration partly inspired by Holtan et al. (5)]. process in which the presence of Treg cells is favorable, cancer is a pathophysiological scenario in which the suppression of a potential anti-tumor response is undesirable. However, as will This highlights the importance of broadening our understanding be discussed in later sections, this distinction is not always of the function of Treg cells across diﬀerent physiological obvious, and in some cancer settings, the presence of Treg and pathophysiological settings, such as pregnancy, pregnancy cells and thus the control of the inﬂammatory environment can complications, and cancer, in order to develop and oﬀer the probably be advantageous seen from an anti-tumor perspective. right therapeutic treatment. This review provides an overview Frontiers in Immunology | www.frontiersin.org 2 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer of current knowledge on the tolerogenic function of Tregs in Regulatory T Cell Subsets immunological mechanisms during pregnancy and cancer, and Tregs are found throughout the body, where they modulate in relation to possible therapeutic intervention of both human activities of cellular components of both the innate and adaptive malignancies and reproduction. immune system. CD4 Tregs can be divided into distinct subsets according to unique functional and homeostatic properties (Figure 2). FoxP3 Tregs originating from the thymus, where they have diﬀerentiated during T cell ontogenesis, are referred REGULATORY T CELLS to as natural or thymic (t) Tregs, and Tregs developed in the Regulatory T cells are a T lymphocyte population with periphery or in vitro from conventional CD4 T cells are referred immune suppressive properties responsible for maintaining to as peripheral or induced (i) Tregs (30, 31). Furthermore, there antigen-speciﬁc T cell tolerance. Tregs comprise both are two phenotypically distinct immunosuppressive subtypes + + + CD4 and CD8 subtypes. Whereas, CD4 Treg cells of the iTregs, namely the IL-10 producing T regulatory type have been extensively studied, lack of clear markers to 1 (Tr1) cells and the TGF-β-producing Th3 cells (32, 33). It + + distinguish CD8 Tregs from conventional CD8 T cells remains to be determined, whether the diﬀerent subsets of Tregs has led to unsatisfactory characterization of origin, function belong to unique cell lineages, or whether they only reﬂect the and phenotype (11, 12). Therefore, this review will focus plasticity of the Treg population and represent an altered state mainly on CD4 regulatory T cell subsets, and “Treg” or of diﬀerentiation (34). Furthermore, it is debated, whether iTregs “regulatory T cell” will refer to CD4 regulatory T cells, unless can arise from any conventional T cell or from a pre-committed stated otherwise. cell lineage (35). + + Normally, CD4 Tregs constitute 5–10% of the total CD4 Both tymus-derived tTregs and peripheral iTregs T cell population and are derived from thymic precursors (13). are characterized by high expression of CD25, FoxP3, Regulatory T cells where ﬁrst described in 1972, where Gershon cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and et al. showed that T cells were capable of suppressing the antigen- glucocorticoid-induced tumor necrosis factor-related receptor induced response of other T cells directly without the mediation (GITR), but iTregs have been shown to express reduced levels of of B cells and their production of antibodies (14). However, it was programmed cell death protein 1 (PD-1), CD73, the transcription not until 1995 that Tregs were identiﬁed as a specialized CD4 factor Helios and the surface antigen neutropilin-1 (Nrp1) (36). T cell population expressing CD25 (15). Subsequently, several Both Helios and Nrp1 have been suggested as markers for + + in vitro studies showed that CD4 CD25 T cells represent distinguishing between tTregs and iTregs, but the speciﬁcity a distinct lineage of naturally anergic and suppressive cells of these markers is a current matter of debate (36–39). Mice (16, 17). The original studies on characterization of Tregs studies have suggested that GITR is involved in the generation were performed in mice. However, in 2001 a T cell population and maturation of FoxP3 tTregs and Tr1-like cells (40, 41). with identical immunosuppressive properties was identiﬁed in Furthermore, it has been suggested that GITR is a marker of humans (18–21). In 2003, the transcription factor forkhead active Tregs (42). In addition to the above mentioned markers, box protein P3 (FoxP3) was identiﬁed as a potent marker for expression of the ATP-degrading enzymes CD39 and CD73 on Tregs in several mouse studies. FoxP3 deﬁciency caused a fatal the surface of Tregs have been increasingly used as markers of lymphoproliferative disease demonstrating that the transcription Tregs and might contribute to the suppressive activity together factor was essential for development of Tregs and for their with expression of the immunoglobulin-like transmembrane immunosuppressive function (22–24). The requirement of FoxP3 protein LAG3 (Figure 3) (43–46). + + expression for immunosuppression was later demonstrated in Thymic CD4 CD25 tTregs are developed in the thymus from CD4 precursors. Development of tTregs or conventional humans (25). + + Based on these discoveries, expression of CD25 on the cell CD4 T cell populations from the CD4 precursor depends surface and presence of the intracellular transcription factor on the aﬃnity of the T cell receptor (TCR) for self-antigens: low aﬃnity leads to positive selection of conventional CD4 T FoxP3 became the key characteristics of the Treg population. cells, whereas medium aﬃnity interactions with thymic epithelial The mutual expression of these markers is commonly used for + + cells lead to development of CD4 CD25 tTregs (47–49). identiﬁcation of Tregs in experimental settings. Conversely, some Immunosuppression by tTregs require activation via their TCR. studies suggest a lack of correlation between CD25 and FoxP3 in When activated, the suppressor eﬀector function is independent human and mice CD4 T cells (24, 26). Alternatively, Liu et al. of antigen-speciﬁcity. Conversely, inhibition of the eﬀector T found that low expression of CD127 serves as a good biomarker (Teﬀ) cell population is mainly depending on cell contact and for human Tregs together with CD25 expression (26), although independent of suppressive cytokines (18, 50). The result of tTreg other studies have not been able to ﬁnd a clear correlation lo mediated immune regulation is reduced number of Teﬀ cells and between CD127 and FoxP3 expression (27). In addition, several + − − altered activity and traﬃcking pattern of activated Teﬀ cells (37). sub-populations of CD4 CD25 FoxP3 Tregs have also been identiﬁed (28). Hence, the most speciﬁc marker still remains In vitro or in vivo induced iTregs can be diﬀerentiated from naïve CD4 T cells in response to antigen, CD28, TGF-β and a matter of debate. Nevertheless, as expression of FoxP3 has IL-2 stimulation, and mediate their suppressive activity mainly been shown to correlate with suppressor activity irrespectively of via secretion of cytokines such as IL-10 and TGF-β that reduce CD25 expression many consider FoxP3 as the most speciﬁc Treg the capacity of dendritic cells (DCs) to present antigen (37). marker (29). Frontiers in Immunology | www.frontiersin.org 3 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer + + FIGURE 2 | Characteristics of CD4 regulatory T cell subsets. Different subsets of CD4 regulatory T (Treg) cells exist and play a role in the establishment of tolerance in different physiological and pathophysiological settings. Thymic (t)Tregs and HLA-G Tregs are developed in the thymus in response to self-antigen, whereas induced (i)Tregs, Tr1 cells and Th3 cells are developed in the periphery in response to antigen presentation and cytokines. Natural Treg and iTregs are + − − characterized by CD25 and FoxP3 expression, while HLA-G Tregs, Tr1, and Th3 cells are CD25 FoxP3 , although controversies do exist (see the text for details). The thymus-derived Treg cells mediate their effect mainly through cell contact. In contrast, immune suppression by peripheral induced iTreg, Tr1, and Th3 cells are mediated mainly via secretion of the anti-inﬂammatory cytokines TGF-β and IL-10. As for the iTregs, the peripheral Tr1 and Th3 subsets are also the suppressive eﬀect of HLA-G expression was conﬁrmed + + + induced in the periphery from the conventional CD4 T cells. by neutralization of HLA-G on CD4 HLA-G cells, which In contrast to tTregs and iTregs, expression of CD25 and FoxP3 reduced their suppressive capacity. The cells were, however, not in Tr1 and Th3 cells are controversial (51–53). Tr1 and Th3 expressing CD25 and FoxP3, like previously described Tregs. have been identiﬁed as FoxP3- and CD25-negative, although it When comparing the properties and molecular characteristics + + + + + seems that expression of both markers can be upregulated in of CD4 HLA-G cells and CD4 CD25 FoxP3 cells, there response to activation (53, 54). The Tr1 cells were ﬁrst described is a clear distinction between the phenotype and the cytokine by Groux et al. (55), who found that Tr1 cells are activated by proﬁle of the two cell populations (62). The suppressive function + + + IL-10 and suppress the proliferation of CD4 cells in response to of CD4 HLA-G cells is mediated mainly by secretion of antigen (55). Presence of IFN-α further enhances IL-10-mediated soluble HLA-G and high levels of IL-10 and IL-35, while + + + induction of Tr1 activation and diﬀerentiation (56). The Tr1 CD4 CD25 FoxP3 cells seems to work mainly in a cell-contact + + cells constitute a low proliferating subset that produces high dependent manner. Furthermore, CD4 HLA-G cells are clearly levels of IL-10, low levels of TGF-β and marginal or no IL-2 and distinct from Tr1 cells as they do not require the presence IL-4 (55, 57). Th3 cells are activated upon antigen stimulation of other cell types (63). The identiﬁcation of a novel T cell (58). However, TGF-β also promote the induction of Th3 cells population with regulatory properties expressing HLA-G on the from CD4 T cells, which can be further enhanced by the surface has led to the notion of a new subset belonging to the presence of IL-10 and IL-4 (32). When active, the Th3 cells have repertoire of suppressor T cells (64). As these cells have a similar + + + suppressive properties for Th1 and Th2 cells through secretion of function as CD4 CD25 FoxP3 Tregs, their role in peripheral TGF-β (59, 60). immune regulation is increasingly recognized. However, whether A new subset of regulatory T cells have emerged during the they should be identiﬁed as traditional regulatory T cells as the recent years deﬁned by expression of the immunosuppressive classical Tregs is somehow controversial. Human Leukocyte Antigen (HLA) molecule HLA-G (Figure 2). No universal agreement on which factors that can be used In 2007, Feger et al. identiﬁed HLA-G T cells among CD4 and to diﬀerentiate tTregs from iTregs seems to exist. Moreover, CD8 single-positive cells in the peripheral blood and thymus it is important to note that most studies have used shared from healthy individuals (61). The cell population showed markers such as FoxP3, CD25, and CD127 for identiﬁcation of reduced proliferation to allogeneic and polyclonal stimuli and Treg cells, thus do not diﬀerentiate between tTregs and iTregs, Frontiers in Immunology | www.frontiersin.org 4 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer FIGURE 3 | Schematic overview of similarities in Treg function in central tolerance, fetal tolerance, and cancer tolerance. Tolerance play an important role in both fetal and cancer tolerance. Tregs are developed by presentation of antigens of fetal (fAg) or tumor (tAg) origin. Many tumor cells and fetal extravillous trophoblast (EVT) cells have both diminished or no expression of MHC class II and classical MHC class I molecules. Instead, the EVT cells and some cancer cells express HLA class Ib molecules, e.g., the immune modulatory non-classical HLA-G. HLA-G is able to protect fetal and tumor cells from NK cell lysis, as well as according to a few studies to induce Treg formation. Fetal EVTs and tumor cells are also able to contribute to Treg homeostasis by inhibiting effector T cell activation and proliferation through PD-L1/PD-1 and indoleamine-2,3-dioxygenase (IDO) expression. Decidual (d)NK cells further contribute by inhibiting Th17 responses by IFN-γ expression. Fetal EVTs also express cytokines, e.g., IL-10 and TGF-β that induce Treg development. Tregs limit Teff cells and promote their own proliferation and survival through direct engagement with Teff cells, e.g., via PD-L1/PD-1, by the conversion of ATP to Adenosine (Ado) and cytokine secretion. and by that deﬁnition also exclude any immunosuppressive THE ROLE OF TREGS IN CANCER − + FoxP3 T cells, such as the Tr1, Th3, and HLA-G Tregs. The progression of cancer is controlled by a complex biologic The following section will focus on studies using FoxP3, system that is highly dependent on interaction between the CD25, and CD127, and the term “Treg” will therefore refer to malignant cells and the surrounding tumor microenvironment regulatory CD4 T cells regardless of origin, unless speciﬁcally comprising the immune cells. Various types of immune cells stated otherwise. Frontiers in Immunology | www.frontiersin.org 5 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer can inﬁltrate the tumor and may inﬂuence tumors diﬀerently Mechanisms of Treg-Mediated depending on their histological and molecular type, their stage, Immunosuppression in Cancer the microenvironment of the organ in which they occur, and Several mechanisms contribute to the accumulation of Tregs the nature of the tumor (Figure 1) (65). Immune eﬀector within neoplastic lesions including increased inﬁltration, cells can detect and destroy cancer cells preventing tumor local expansion, survival advantage, and development from formation by means of both the innate and adaptive immune conventional CD4 cells (30). All of these mediated through compartments. However, the anti-tumor activity of the immune signaling with other cells and through diﬀerent signaling cells are often downregulated by tumor-derived signals leading molecules (Figure 3). to immune escape. A large number of preclinical models Studies on mice deﬁcient of key markers of Tregs, including have demonstrated the inﬂuence of Tregs in development and IL-10, CTLA-4, GITR, or PD-1 that develop severe immune- progression of several types of malignancies, and Tregs are related disorders indicate that these molecules are crucial for generally believed to be a signiﬁcant contributor to tumor Treg function in a cancer setting. The CTLA-4 receptor is a immune escape (66, 67). A widely accepted hypothesis is that negative regulator of T cell responses functioning as an immune recruitment of tumor-inﬁltrating Tregs with immunosuppressive checkpoint. Leach et al. was the ﬁrst to show that blockades of properties enable the malignant cells to evade the host immune the inhibitory signals of CTLA-4 enhance antitumor immunity response (68). in mice (97). Proof that this was also the case in humans came Increased numbers of tumor-inﬁltrating Tregs have in 2003 in a clinical investigation, where CTLA-4 blockade been demonstrated in patients with ovarian (69), liver (70), increased tumor immunity in some previously vaccinated melanoma (68), gastric, and esophageal cancer (71), in melanoma and ovarian carcinoma patients (98). Much research chronic lymphocytic leukemia (72), and in breast cancer, have been performed on the mechanism of antitumor immunity where it is associated with a more aggressive phenotype elicited by CTLA-4 blockade and one study has shown that (73). The same is seen in gastric and esophageal cancers, Treg-speciﬁc CTLA-4 deﬁciency results in downregulation of where Tregs increase with disease stage suggesting induced CD80 and CD86 on DCs leading to loss of immunosuppression expansion of Tregs by tumor-related factors (74). Furthermore, (99). This happens in part through abrogated expression of the Treg numbers are also increased in the peripheral blood immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) of patients with breast, pancreatic (75), liver (70), gastric, by the DCs (100). When it comes to cancer, IDO is expressed and esophageal cancer (71) in comparison with blood from also within solid tumors from both tumor and stromal cells, healthy individuals. where it under normal conditions restrains an inﬂammatory Various studies have tried to identify the role of Tregs in reaction against cancer cells by degradation of tryptophan and immune evasion, and as it has become clear that the eﬀect recruitment of Tregs (101, 102). Another commonly known of Tregs on tumor progression vary according to the tumor checkpoint molecule is PD-1. PD-1 is a receptor expressed on type, the prognostic signiﬁcance of Treg inﬁltration remains a activated T cells, B cells, and myeloid cells. One of the early matter of debate. An overview of the clinical signiﬁcance in proofs of PD-1 being involved in maintenance of self-tolerance a range of cancers is provided in Table 1. In connection to came in 1999, where a knock-out mouse model showed that a the role of Tregs in evading immune recognition, a common defect in the PD-1 gene speciﬁcally predisposes to development presumption is that high numbers of Tregs within lymphoid of lupus-like autoimmune disease suggesting that PD-1 serves inﬁltrates can be predictive of relapse and dead. However, the as a negative regulator of immune responses (103). The same prognostic value of Tregs is somehow controversial as in some was seen in humans, where a study by Freeman et al. revealed cancers Tregs inﬁltration may exert a beneﬁcial role or can that engagement of PD-1 by its ligand PD-L1 led to inhibition of have both a negative and positive eﬀect on disease progression T cell receptor-mediated lymphocyte proliferation and cytokine and survival. The negative eﬀect on survival is observed in secretion (104). Furthermore, blockade of PD-1 seems to enhance pancreatic (87), liver (90), gastric, and esophageal cancer (74). recruitment of Teﬀ cells in intrasplenic tumors and prevent metastatic spread of several diﬀerent cancers (105). The crucial It is though more likely to observe opposing roles of Tregs in terms of survival in a wide range of cancer types such as role of CTLA-4 and PD-1 in regulation of a tolerogenic immune response opens up for a blockage of both checkpoint molecules cases of ovarian carcinoma (69, 76), colorectal cancer (85, 86), that may have great therapeutic potential in terms of activating melanoma (88), breast cancer (77–84), head and neck squamous an immune response against the cancer cells. Whereas, both cell carcinoma (91, 92), and lymphoma (93–96), where a high CTLA-4 and PD-1 function as negative regulators, GITR function frequency of Tregs improve disease-speciﬁc survival in some as a co-stimulatory receptor, leading to activation, proliferation patients and in others favors immune escape and tumor growth. and cytokine production in both Teﬀ and Treg cell populations Furthermore, in some patients there is no correlation between (106–108). As mentioned, GITR is expressed in high levels by Treg inﬁltration and disease progression at all (89). The reason for this discrepancy in the prognostic value of Treg inﬁltration Tregs, and has been shown to be increased in several cancer forms including breast cancer (42, 109, 110). Engagement of might be related to the diﬀerent nature of the cancers and the eﬀect of inﬂammation on tumor growth, but could also GITR on Treg cells has been shown to inhibit their suppressive function, and rendering Teﬀ unresponsive to Treg-mediated be dependent on the presence of diﬀerent Treg subsets in the suppression (106, 107). However, it has also been shown that diﬀerent malignancies. Frontiers in Immunology | www.frontiersin.org 6 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer Frontiers in Immunology | www.frontiersin.org 7 May 2019 | Volume 10 | Article 911 TABLE 1 | Examples of clinical signiﬁcance of Tregs in the tumor microenvironment. References Cancer Presence Treg deﬁnition Effect on clinical outcome Comment of Tregs Good/bad How + + + Curiel et al. (69) Ovarian carcinoma High CD4 CD25 FoxP3 Bad Reduced survival Treg cells suppress tumor-speciﬁc T cell immunity and contribute to growth of human tumors in vivo Milne et al. (76) Ovarian carcinoma High FoxP3 Good Increased disease-speciﬁc survival Tregs is associated with survival only in high-grade serous tumors from optimally debulked patients a + hi Gobert et al. (77) Breast cancer High CD4 CD25 Bad Higher risk of relapse and death Tregs are selectively recruited within lymphoid inﬁltrates and activated lo + CD127 FoxP3 by mature dendritic cells through tumor-associated antigens a + Demir et al. (78) Breast cancer High FoxP3 Bad Shorter overall survival The density of Treg inﬁltration before chemotherapy is a strong predictor for survival a + Sun et al. (79) Breast cancer High FoxP3 Bad Shorter disease-free survival Signiﬁcant correlation between expression of PD-1 in tumor-associated immune cells and FoxP3 cells − + + + West et al. (80) ER breast cancer High FoxP3 Good Prolonged recurrence-free survival FoxP3 Tregs are positively correlated with CD8 cytotoxic T cells and anti-tumor immunity + + Bates et al. (81) ER breast cancer High FoxP3 Bad Shorter relapse-free and overall High Treg numbers associated with high-grade tumors and lymph node survival involvement ER breast cancer - No impact + + + Liu et al. (82) ER breast cancer High FoxP3 Bad Poor survival High FoxP3 cell numbers are associated with young age, high grade, − + ER breast cancer Good Improved survival ER negativity, concurrent CD8 T cell inﬁltration, and HER2 positive ER subtypes + + + + Lee et al. (83) Triple-negative breast cancer High CD4 CD25 FoxP3 Good Improved survival High inﬁltration of FoxP3 Tregs is an independent prognostic factor for overall survival and progression free survival Liu et al. (84) Triple-negative breast cancer High FoxP3 Good Better overall and disease-free Elevated expression of Treg and immune-related genes is associated survival with more favorable outcome Frey et al. (85) Colorectal cancer High FoxP3 Good Improve disease-speciﬁc survival High frequency of tumor-inﬁltrating Tregs is associated with early T stage, tumor location, and increased 5-year survival rate + + + Chang et al. (86) Colorectal cancer High CD4 CD25 FoxP3 Bad Favor tumor growth CCL5/CCR5 signaling recruits Tregs to tumors and enhance their ability to kill antitumor CD8 T cells leading to immune escape + hi Kono et al. (74) Gastric and esophageal cancer High CD4 CD25 Bad Poor survival rate After curative resections of gastric cancers, the proportion of Tregs is signiﬁcantly reduced. In cases with recurrent tumors, levels increase again + + + Hiraoka et al. (87) Pancreatic ductal High CD4 CD25 FoxP3 Bad Poor prognosis The prevalence of Tregs increase signiﬁcantly during the progression of adenocarcinoma premalignant lesions + + + Miracco et al. (88) Primary cutaneous melanoma High CD4 CD25 FoxP3 Bad Predictive of recurrence The percentage of Tregs, both among tumor cells, inside tumor parenchyma and at periphery, is signiﬁcantly higher in cases that recurred Ladányi et al. (89) Primary cutaneous melanoma High FoxP3 - No prognostic impact The degree of Treg inﬁltration do not correlate with tumor thickness, metastasis, or survival. + + + Kobayashi et al. (90) Hepatocellular carcinoma High CD4 CD25 FoxP3 Bad Lower survival The prevalence of Tregs increase in a stepwise manner during the progression of hepatocarcinogenesis + + + + Badoual et al. (91) Head and neck squamous cell High CD4 FoxP3 Good Favorable Regulatory CD4 FoxP3 T cells are positively correlated with carcinoma locoregional control (Continued) Jørgensen et al. Tregs in Pregnancy and Cancer GITR induces IL-10 production, that if blocked leads to further GITR-mediated proliferation (108), leaving the exact role of GITR controversial. As shown in a study, the function of GITR on Treg cells is most likely context-dependent and rely on the model used to study its function, as well as the immunological milieu (111). Nevertheless, GITR is, like CTLA-4 and PD-1, an attractive target for immunotherapy, and GITR triggering using agonist antibodies and Fc-GITRL abrogates Treg-mediated suppression (106). Whereas, the function of tTregs is mainly cell-cell contact- dependent, the secretion of soluble factors, such as cytokines by iTregs and other Treg subtypes is essential for their hi function (Figure 2). IL-10 is a cytokine produced by CD44 Tregs and plays a central role both in parasitic infections (112), intestinal inﬂammation (113), and cancer (114) again emphasizing the involvement of similar mechanisms in diﬀerent pathophysiological conditions. In addition to IL-10, TGF-β is also produced by peripheral Tregs. Both IL-10 and TGF-β have pleiotrophic functions and have been implicated in both cancer progression as well as clearance [reviewed by (115)]. The eﬀect of IL-10 and TGF-β therefore most likely depends on the speciﬁc cancer type, and therapy targeting these cytokines should be done with careful considerations. Considering that Treg cells hi are deﬁned as CD25 , the high aﬃnity IL-2Rα chain, IL-2 is another cytokine central to both thymic and peripheral Treg development, function and homeostasis (116, 117). In contrast, the IL-7 receptor α chain, CD127, is low or absent in human Tregs, indicating that IL-7 is not required for Treg function, although a study in mice has suggested that IL-7 might be involved in early Treg development and in development of + lo CD4 FoxP3 Tregs (116, 117). Another increasingly acknowledged mechanism involved in development of cancer is regulation of the expression of HLA molecules in the tumor microenvironment. Increasing evidence suggest that expression of the classical and non- classical HLA class Ia (HLA-A, HLA-B, HLA-C) and class Ib (HLA-E, HLA-F, HLA-G) molecules inﬂuence immune regulation in a coordinated action with Tregs. This inﬂuence of HLA molecules is seen in multiple physiological and pathophysiological processes as the antigen-presenting capability of HLA molecules play a crucial role in infectious diseases, graft rejection, autoimmunity, reproduction, and cancer. Deregulation of the HLA class I molecules on the cancer cells leads to evasion of the host immune system (118). In a recent study on the prognostic value of tumor-stroma ratio combined with the immune status of the tumor, Vangangelt et al. showed that breast cancer patients with a stroma-low tumor and expression of classical HLA class I molecules have a better prognosis compared to patients with a stroma-high tumor and downregulation of HLA class I (119). Furthermore, when expression of HLA class Ia molecules are concomitantly lost, high expression of HLA-G is associated with a worse relapse-free period in breast cancer (120) and is suggested to facilitate invasion and increase the metastatic capacity of invasive ductal breast carcinoma (121– 123). In gastric cancer, HLA-G expression signiﬁcantly correlates with the presence of Tregs and is predictive of poorer survival (124). Expression of HLA-G and the presence of FoxP3 Frontiers in Immunology | www.frontiersin.org 8 May 2019 | Volume 10 | Article 911 TABLE 1 | Continued References Cancer Presence Treg deﬁnition Effect on clinical outcome Comment of Tregs Good/bad How + inter/hi hi Drennan et al. (92) Head and neck squamous cell High CD4 CD25 Bad Favor tumor progression Elevated frequency and suppressive activity of CD25 Tregs is lo/− carcinoma CD127 associated with advanced tumor stage and metastasis to lymph nodes + + Tzankov et al. (93) Lymphomas High FoxP3 Good Improved survival Increased number of FoxP3 cells positively inﬂuence survival in follicular lymphoma, germinal center-like diffuse large B cell lymphoma, and Hodgkin’s lymphoma Carreras et al. (94) Follicular lymphoma High FoxP3 Good Improved overall survival Patients with low Treg numbers presented more frequently with refractory disease Alvaro et al. (95) Hodgkin’s lymphoma Low FoxP3 Bad Unfavorable Low inﬁltration of Tregs in conjunction with cytotoxic lymphocytes is predictive of unfavorable outcome Schreck et al. (96) Hodgkin’s lymphoma High FoxP3 Bad/– Shorter disease-free survival A high ratio of Treg over Th2 cells is associated with shortened disease-free survival. Tregs have no prognostic impact alone Cohort of patients with advanced/invasive breast cancer irrespective of molecular subtype. Jørgensen et al. Tregs in Pregnancy and Cancer tumor-inﬁltrating lymphocytes is also believed to contribute antigens. Since tumor cells originate from normal cells and to the suppression of eﬀective T cell immune responses in develop within the context of self-tissue, most cancer antigens melanoma (68, 125). We have recently shown an association are self-antigens, and the immune mechanisms that prevent between high HLA-G expression and a high frequency of FoxP3 immune recognition of the tumor cells might function in similar tumor-inﬁltrating lymphocytes in malignant melanoma patients ways as those that prevent autoimmune attack of normal tissue (126). Furthermore, in an in vitro study we have demonstrated (133, 134). This is contrary to pregnancy, where both foreign that the HLA-G choriocarcinoma cell line JEG-3 originating and self-antigens are present from the semi-allogenic fetus and from placenta upregulates Tregs, and that the level of pro- immune suppression is necessary in order to avoid fetal rejection. inﬂammatory cytokines is modulated through HLA-G (127). However, it may be emphasized that cancer cells might eventually A subset of HLA-G-expressing T cells have also been shown to also, due to high mutational rate, express antigens foreign to the play a role in promoting a tolerogenic tumor microenvironment. body that can be recognized by Teﬀ cells. lo + A recent study found a population of CD4 HLA-G T cells A previous study by Wang et al. characterized tumor-speciﬁc associated with development of castration-resistant prostate CD4 T cells derived from a melanoma patient and were cancer in prostate cancer patients after treatment with androgen the ﬁrst to isolate antigen-speciﬁc Tregs, and further showed lo + deprivation therapy. Expansion of the CD4 HLA-G cells that cell-cell contact was required for T cell-mediated immune resulted in impaired immune surveillance and a tumor suppression in agreement with previous studies (135). The group microenvironment that were permissive of tumor growth (128). identiﬁed Tregs speciﬁc for LAGE1 and afterwards the ARCT- + + In pregnancy, CD4 HLA-G T cells have been reported and may 1 peptide (136). Tregs speciﬁc for a broad range of tumor be reduced in pre-eclampsia, although knowledge of a possible antigens including melanoma tissue diﬀerentiation antigens role of this subset is currently very limited (129). and cancer-testis antigen, have been identiﬁed in patients with We are currently investigating how expression of HLA class metastatic melanoma (137), and following studies performed Ia and Ib expression modulate the immune response in breast in colorectal cancer have also revealed tumor antigen-speciﬁc cancer with emphasis on Tregs and Natural Killer (NK) cells. Tregs (138). In colorectal cancer patients undergoing resection, By studying molecular and genetic changes of the immune a high level of FoxP3 Tregs speciﬁc for tumor antigens drives cells in contact with tumor cells we aim to identify molecular immunosuppression and correlates with tumor recurrence and markers associated with the regulatory function of the immune relapse (139). Studies in diabetic mice have revealed a superior cells and clinical outcome. Identiﬁcation of regulatory immune immunosuppressive activity for antigen-speciﬁc Tregs compared cell gene signatures in tumors can be important and relevant to non-speciﬁc Tregs (140, 141). Furthermore, Tregs responding when assessing the clinical course of the disease and prognosis. to self-antigens have also been shown to suppress anti-tumor A recent study focusing on immunogenic gene signatures in immune responses (142, 143). Indications are that Tregs are likely triple-negative breast cancer found a high expression of tumor- to play an important role in cancer immunology and elaborating inﬁltrating lymphocyte gene signatures in the tumor compared on the speciﬁcity of Tregs involved in antitumor responses could to normal tissues and that elevated levels of Treg gene sets be beneﬁcial from a therapeutic perspective. were consistently associated with better overall survival and disease free survival (84). This conﬁrms the controversy about the Immunotherapeutic Intervention in Cancer prognostic signiﬁcance of Tregs in the tumor microenvironment Given the role of Tregs in immune evasion and tumor and emphasizes the importance of research that can elaborate progression, several studies have already suggested that on the role of Tregs in a speciﬁc cancer setting and for the they are promising as therapeutic targets (31). Initially, individual patient. studies focused almost exclusively on the cancer cells as Substantial redundancy may exist in the mechanisms essential targets for therapeutic interventions. However, cancer cells for establishment and maintenance of immune tolerance (46). frequently acquire therapeutic resistance because of inherent Hence more research is necessary to identify mechanisms genetic instability. Hence, working toward manipulation, that could constitute the best targets for immunotherapeutic propagation, and therapeutic application of Tregs will provide treatment strategies. new and improved treatment options. The prognostic eﬀect of Tregs in diﬀerent cancer types is important to take into Antigen-Speciﬁc Tregs consideration when selecting a treatment strategy, and even With the aim to elucidate the role of Tregs in cancer though Tregs appear as an obvious target for anti-tumor development, several studies have found that the Treg response treatment, manipulation of Treg mechanisms is not that simple is an early event preceding the activation of Teﬀ cells (130, and more selective approaches for therapeutic strategies are 131). It was seen many years ago in mice, that a regulatory needed. This involves targeting of speciﬁc Treg subsets and immune response are present early followed by a decrease in the inhibition or activation of Tregs depending on the type of cellular reactivity against the tumor cells and a progressive loss cancer (30). Furthermore, the composition of other immune of immune recognition correlated with progression of tumor cells in the tumor microenvironment must also be taken growth (132). A mechanism by which Tregs are stimulated by the into account when assessing whether a patient will beneﬁt presence of the tumor is via recognition of antigens. from immunotherapy. Recently an immune biomarker task Tumors are believed to present tumor-speciﬁc antigen in the force elicited by the Society for Immunotherapy of Cancer form of neo-epitopes, sometimes known as tumor-associated (SITC) sought to make recommendations of immune-related Frontiers in Immunology | www.frontiersin.org 9 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer biomarkers that can predict the outcome of immunotherapy IDO (158). Hence, clinical trials have been initiated to evaluate in cancer patients (144). They focus on biomarkers in the the eﬃciency of IDO inhibitors and IDO-based vaccinations. A tumor microenvironment, gene expression at the tumor site, combination of pembrolizumab and the selective IDO inhibitor tumor antigens, mutational load, peripheral biomarkers, and Epacadostat initially showed promising results increasing the host-related genetic biomarkers. Overall, this suggest that a anti-tumor activity in patients with advanced solid tumors in combination of personalized diagnostics is necessary in order a phase I/II study (NCT02178722) (161). Unfortunately, no to assess immunocompentence of the individual. In terms of beneﬁt in survival was observed with the combined treatment this, an analysis of immune gene signatures should be feasible to compared to pembrolizumab alone in the following phase III determine the potential for immunotherapy. Liu et al. performed clinical trial (NCT02752074) (162). A clinical phase I study have an extensive analysis on immunogenic signatures in triple- shown that a vaccine with an epitope derived from IDO is well- negative breast cancer on two large-scale breast cancer genomic tolerated in patients with metastatic non-small cell lung cancer datasets. They demonstrated that this type of breast cancer has (NCT01219348) (163). Currently, a clinical phase 2 study is a strong tumor immunogenicity, which suggested that these testing a combination therapy of the PD1 antibody Nivolumab patients could beneﬁt from immunotherapy (84). and a vaccine consisting of PD-L1 and IDO (NCT03047928). Even though treatment by activation of the immune system A third way to enhance anti-tumor eﬀects is to deplete Tregs have proved to be successful it is not without side eﬀects. One of in the tumor microenvironment. Mouse studies have proven the the biggest challenges of targeting Tregs and blocking immune eﬀectiveness of eliminating Tregs by administration of IFN-γ checkpoints is the development of severe system immune-related and the use of IL-2 antibodies in combination with stimulation side eﬀects. Releasing the brake on the immune system can of eﬀector immune cells (140, 164). An ongoing clinical trial lead to a systemic immune activation and might cause extensive is investigating a combination of pembrolizumab and low- autoimmune reactions (31). dose IL-2 in patients with advanced melanoma or renal cell One branch of immunotherapy evolves around the idea cancer (NCT03111901). Furthermore, a phase I/II study have + + of activating the immune system targeting the regulatory shown that CD4 CD25 Treg depletion improves the graft- mechanisms that suppress an immune response against the vs.-tumor therapeutic eﬀect of donor lymphocyte infusion in cancer. Especially, cancer therapy by inhibition of negative patients suﬀering from hematopoietic malignancies and relapse immune regulation has proved very successful within recent after standard allogeneic hematopoietic stem cell transplantation years in the form of immune checkpoint inhibitors and are (NCT00987987) (165). currently used in cancer immunotherapy. Discovery of the Another branch of immunotherapy focuses on targeting two checkpoint molecules CTLA-4 and PD-1 that function as tumor antigens. Recognizing an increased activity for Tregs brakes on the immune system has led to a new approach for that are antigen-speciﬁc gave the idea that Tregs could also be treating cancer patients. Ipilimumab and tremelimumab are two exploited to target cancer cells. Expression of chimeric antigen well-characterized anti-CTLA-4 antibodies, the ﬁrst approved receptor (CAR) T cells to engineer T cells with antigen-speciﬁcity for treatment of malignant melanoma, colorectal cancer, and toward cancer cells have already oﬀered a promising strategy to renal cell carcinoma and the second being tested in clinical target diseases with extensive immune activation. This directs the trials on colorectal cancer and lung cancer patients (145–151). attention to a similar approach for Tregs with the possibility that Pembrolizumab is an anti-PD-1 drug approved for treatment of CAR Tregs could be used in Treg-mediated therapy reducing a multiple cancers including cervical cancer and melanoma (152– generalized immunosuppression (35). In terms of this, studies + + 155). Nivolumab is another anti-PD1 drug that in combination have shown that it is possible to isolate CD4 CD25 cells with with ipilimumab is used as ﬁrst-line treatment of melanoma immunosuppressive function from peripheral blood and expand being more eﬀective than either agent alone (156). Furthermore, them in vitro without loss of function, which represent a major nivolumab is shown to have a higher eﬃcacy as compared advance toward the therapeutic use of these cells in T cell- to chemotherapy in patients with melanoma, who progressed mediated diseases (166). So far, engineered Tregs have been after CTLA-4 treatment (157). These immunotherapies have shown to target the central nervous system reducing symptoms of emphasized how manipulation of immune regulation is essential multiple sclerosis by suppression of inﬂammation and in colitis for eradicating tumors. patients CAR T cells could hinder development of colorectal Another strategy of breaking the tolerance to tumor tissue cancer (167, 168). This indicate that the use of engineered Tregs is to inhibit the IDO pathway. Studies show that elimination is preferred in cancers with prominent inﬂammation and where of IDO-positive immunosuppressive cells change the regulatory immune suppression will have a beneﬁcial role in preventing microenvironment (158). Furthermore, it was found that 1- tumor progression. Moreover, a new study suggest a promising methyl-tryptophan isomers capable of blocking IDO activity is role for CAR T cells in delivery of checkpoint inhibitors. Mouse eﬀective in reversing the suppression of T cells promoted by CAR T cells was modiﬁed to secrete PD-1 blocking single-chain DCs (159). Combined with other immune activating drugs, IDO variable fragments and was shown to enhance the anti-tumor might also enhance the eﬃcacy of immunotherapy by preventing function in mouse models of hematologic and solid tumor (169). counter-regulation in response to immune activation (160). Hence, the targeted delivery of immune checkpoint inhibitors Combining induction of IDO-speciﬁc immune responses with or expression of other immunomodulatory molecules could anti-cancer immune therapy has the synergistic potential to both prevent systemic blockade, eventually improving treatment and eliminate cancer cells and immune suppressive cells expressing minimizing adverse side eﬀects. Frontiers in Immunology | www.frontiersin.org 10 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer THE ROLE OF TREGS IN REPRODUCTIVE (183). Roughly speaking, there are two compartments in the placenta in which maternal immune cells interact with the fetal BIOLOGY cells; the intervillous space and the decidua. The interactions between the fetal trophoblast cells and the maternal T cells will With the inheritance of half of the genes from the father, the fetus is considered to be semi-allogenic in an immunological sense. be diﬀerent at the two places. The intervillous space is the space This results in the immunological paradox in which the maternal between the anchoring villi, ﬂooded with maternal blood that allows exchange of nutrients. The syncytiotrophoblast cells here immune system has to be able to tolerate the presence of the foreign paternally derived antigens for a successful pregnancy lack the expression of all MHC/HLA molecules and should, in theory, not be able to interact with the maternal T cells to take place. Initially, a shift from a Th1 pro-inﬂammatory response toward an anti-inﬂammatory Th2 response has been (184). It has been suggested that the main role of the T cells located here is to protect mother and fetus against infectious the central paradigm to explain the generation of fetal tolerance (170). However, during normal pregnancy the decidua contains a pathogens (185). However, it should be noted that maternal + + antigen presenting cells (APCs) are still able to induce an adaptive decreased CD4 /CD8 ratio compared to the peripheral blood, and decreased numbers of CCR6 Th1, Th2, and Th17 cells, immune response by presenting paternal antigens despite the − + hi +/hi lack of MHC/HLA on the syncytiotrophoblast cells (186). In while CCR6 Th1 cells and CD4 CD25 FoxP3 Tregs are increased (171, 172). This reﬂects a much more complex scenario, contrast, invading extravillous trophoblasts (EVTs) present in the decidua express a unique combination of HLA-C and the non- and are now explained as a balance between Th1, Th2, Th17, and classical HLA-E, -F, and -G molecules, enabling them to elicit regulatory responses involving both innate and adaptive immune cells (173, 174). Moreover, recently it has been proposed that the immunosuppression and induce tolerance. The expression of a polymorphic paternally inherited HLA-C molecule on EVT has immune system plays diﬀerent roles in the diﬀerent phases of pregnancy; an inﬂammatory response seems necessary for the the potential to induce alloreactivity toward the fetal-derived cells. However, HLA-C is only expressed at a level of ∼10% of implantation of the blastocyst, while there is an establishment of a tolerogenic milieu for maintenance of the pregnancy, and HLA-A and -B, and HLA-C interacts both with T cells and NK cells through KIRs (7, 184). In addition to the local immune yet another shift toward inﬂammation at parturition (174, 175). To constrain inﬂammation and avoid fetal rejection, several changes happening in the placenta during pregnancy, peripheral tolerogenesis is also observed (187). It is not yet fully understood mechanisms have developed in which increasing focus has been giving to the role and function of the anti-inﬂammatory whether the peripheral changes reﬂects the local changes or if there is a separate systemic response to pregnancy, e.g., through properties of the regulatory Tregs (10, 173, 174, 176), which is described in the next section. interaction with shed trophoblast debris or exosomes. Although maternal Teﬀ cells are fully capable of recognizing Many studies have shown the importance of Tregs for pregnancy (10, 173, 174, 176). Tregs and FoxP3 mRNA have paternal antigens and become activated, this does not lead to rejection of the fetus (177, 178). Tafuri et al. were also able to been found in the endometrium throughout the menstrual cycle, increasing in the follicular/estrus phase and thereby show that paternally derived tumor cells were able to persist during pregnancy independent of antibody response, but was the receptive phase, suggesting that the uterus is preparing for pregnancy also involving immunomodulatory changes rejected after parturition (178). This indicates a pivotal role for establishment of a temporal state of tolerance against the (188, 189). Some studies might also indicate that the female immune system is primed for pregnancy through contact with paternal antigens during pregnancy, and thus an important role for Tregs (178, 179). Several mechanisms have been antigens and immunomodulatory molecules present in the seminal plasma during coitus (190). In mice, the CD4 and identiﬁed that protect the fetus from immune attack, including attenuated expression of polymorphic Major Histocompatibility CD8 Treg populations expand immediately after mating due Complex (MHC)/HLA proteins as well as expression of the to activation by paternally derived antigens present in the seminal ﬂuid (186). Pregnant women have a higher level of nearly monomorphic HLA class Ib molecules, release of anti- inﬂammatory hormones, cytokines, and immunomodulatory peripheral Tregs compared to non-pregnant women with Treg numbers peaking during ﬁrst and second trimester (191–194). molecules by the placenta, and suppression of allo-reactive responses (173). Fetal tolerance during pregnancy seems to be a In parallel, higher levels of Tregs can also be observed in certain cancer patients compared with healthy individuals as discussed balance between clonal exhaustion (i.e., deletion or inactivation) of allo-reactive T cells and immune regulation—a phenomenon brieﬂy previously. Moreover, it has been shown that women with infertility problems and women experiencing recurrent also seen in transplantation (180–182). During the formation of the maternal-fetal interphase fetal pregnancy loss (RPL) in ﬁrst trimester have reduced number of trophoblast cells will invade into the maternal decidua harboring Tregs and FoxP3 mRNA, indicating an early role for Tregs in maternal immune cells to form the placenta. In parallel, the the establishment of pregnancy (188, 195). The role of Tregs in tumor microenvironment can be seen as a pathological situation connection with the uterine (u)NK cells in the endometrium of with tumor cells with a distinct and possible non-self-phenotype infertile women has been thoroughly described in a recent review in close contact with immune cells (Figure 1). The placenta by Kofod et al. (196). Reduced numbers of Tregs, and increased is regarded as an immunological privileged site and is the number of CD8 T cells and Th17 cells, have also been associated source of many immunomodulatory molecules, hormones and with pregnancy complications such as pre-eclampsia (PE) and cytokines that contributes to establishment of fetal tolerance RPL (191, 192, 197). In mice, depletion of Tregs using anti-CD25 Frontiers in Immunology | www.frontiersin.org 11 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer monoclonal antibodies at the time of implantation resulted in in the human decidua (204, 205), Tregs seem to be recruited to poor implantation and fetal reabsorption in allogeneic, but not the uterus during estrus and in early pregnancy by chemokines in syngeneic pregnancies. In contrast, no eﬀect was observed such as CCL1, CCL4, CCL17, and CCL22 (171, 189, 206). on either pregnancy outcome, blood pressure or urinary protein In the pregnant mouse, the chemokine receptor CCR5 + + levels, when Tregs were depleted later in pregnancy (182). recognizing CCL4 is expressed by 70% of the CD4 CD25 This conﬁrms the proposed role for the Tregs in creating a Tregs, and interaction of CCR8 with CCL1 has been shown tolerogenic environment toward the paternal allo-antigens early to enhance the immunosuppressive function of the Tregs by in implantation and pregnancy. It has been suggested that both inducing FoxP3 expression and IL-10, TGF-β and Granzyme B thymic and induced peripheral Tregs play important roles in production (189, 207). pregnancy. Mice studies have shown that pre-existing thymic The fetal trophoblast cells also express and release a number memory/activated Tregs speciﬁc for self-antigens are present very of immunomodulatory molecules that contribute to the Treg early in pregnancy and thus play a role in implantation, whereas balance. Importantly, as seen in cancer and discussed above, depletion of peripheral Tregs leads to increased abortion later in the attenuated expression of polymorphic HLA molecules in hi pregnancy (198). In human ﬁrst trimester decidua, FoxP3 Tregs addition to the expression of the non-classical HLA class Ib, + + + with a similar phenotype (CD45RO HLA-DR CTLA-4 ) have which show very limited polymorphism, are believed to protect been identiﬁed (171). Analysis of Treg cells from term placenta the fetal trophoblast cells from a direct cytotoxic response by tissue also showed that these cells expressed GITR and had higher maternal Teﬀ and NK cells (7, 208–210). Moreover, interactions expression of CD25, CTLA-4, and CD69 in comparison to their with HLA-G have been shown to induce the development of peripheral counterparts, indicating an activated phenotype (194). immunosuppressive CD4 T cells and suppress APCs (211, Lastly, recent studies have shown that pregnancy also leads to 212). A special CD8αα Treg cell that speciﬁcally identiﬁes the generation of both eﬀector memory and central memory Qa-1a (equivalent to the human MHC class Ib molecule HLA- + + + CD4 and CD8 T cells that persist after pregnancy (199). The E), has been found to control activated CD4 T cells in development of memory Tregs after pregnancy and their possible mice (213). Furthermore, CD8αα cells have been shown to role for subsequent pregnancies remains to be elucidated. inﬁltrate the ovaries during ovulation. Although the origin and Despite these observations, the exact role of the Tregs are still characterization of the nature of the CD8αα cell was unclear, poorly understood. Also, the activation and generation of Tregs the CD8αα cells seemed to originate from the thymus and are dependent on recognition of antigen. Although mice studies responded to the thymus-expressed chemokine (TECK), which is have shown that allo-reactive T cells are clonally deleted and important for T cell development. Importantly, it was found that inactivated in a paternal antigen-speciﬁc manner, and like-wise, depletion of the CD8αα cells resulted in impaired fertility of the that Tregs recognizing paternal antigens are generated during female mice, suggesting a role in the establishment of pregnancy pregnancy, the exact nature and origin of the antigen responsible (214). The role of CD8 Tregs in pregnancy is unclear, however, for generation of pregnancy-speciﬁc Tregs in natural settings it would be interesting to study if any similar cell populations are are sparse (180, 182). More studies are needed to understand, important for pregnancy in humans. whether the role of the Tregs is speciﬁcally to limit harmful pro- Negative regulators such as PD-L1 (215), the TNF family inﬂammatory/Th1 and allo-reactive immune responses toward members FasL (CD95L or Apoptosis Antigen (APO)-1L) and the fetus, or whether the generation and function of the Tregs tumor necrosis factor-related apoptosis inducing ligand (TRAIL; are to limit general inﬂammatory responses in an environment CD235/APO-2L) (216–218) and IDO (219, 220) are also of tissue repair owed to the growing placenta (176). expressed by the trophoblast cells. These molecules, as described in previous sections, contribute to T cell homeostasis by inducing apoptosis in allo-reactive Teﬀ cells. Moreover, the trophoblast Mechanisms of Treg-Mediated cells also secrete IL-10 and TGF-β that contribute to Treg Immunosuppression in Pregnancy recruitment and diﬀerentiation (221, 222), of which IL-10 also The mechanisms of fetal tolerance in pregnancy are many has been shown to upregulate HLA-G, thus further contributing and cannot exclusively be attributed to the generation of to the Treg balance (223). As mentioned earlier, IL-10 and TGF- fetal-speciﬁc Tregs. Tolerance include a balance between β play an equally important role during cancer development. clonal deletion and/or inactivation of allo-reactive eﬀector However, in a cancer setting their pleiotrophic function imply cells and immune suppression mediated by regulatory subsets a more unclear eﬀect on the Treg balance depending on comprising both innate cells, such as tolerance-inducing DCs, cancer type. alternatively activated macrophages (M2) and the cytokine- The function of Tregs during pregnancy mirror those bright − producing CD56 CD16 decidual (d)NK cells, and adaptive occurring in the tumor microenvironment, in which Tregs + + cells, including CD4 and CD8 Tregs as well as regulatory B regulate other immune cells present in the maternal-fetal cells. All working together in an impressive network that secures interphase (Figures 1, 3). Tregs limit the eﬀect of allogen-speciﬁc a successful pregnancy (200–202). Teﬀ cells by the expression of CD25, CTLA-4, and the PD- Cells of the endometrium and placenta release L1 pathway and the secretion of IL-10 and TGF-β that induce numerous chemokines that play a role in orchestration of apoptosis and suppress cytotoxicity in recipient cells (171, 173, immunomodulatory cells (203). In contrast to dNK cells, which 176, 197). PD-L1 expression by Treg cells has been found + + − can be generated from CD34 hematopoietic precursors present to inhibit proliferation of CD4 CD25 T cells and suppress Frontiers in Immunology | www.frontiersin.org 12 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer + + expression of the pro-inﬂammatory cytokines IFN-γ and TNF- Tregs show an activated/memory phenotype (CD25 CD45RO ) α (224). PD-1 expression on T cells seem to be increased in as the classical Treg cells, but lack the expression of FoxP3 + + healthy pregnancy compared to non-pregnant women (225), (129). The CD4 HLA-G T cells are found at increased levels while reduced levels of PD-1 and PD-L1 have been suggested in peripheral blood in pregnant women compared with non- to promote Th17 proliferation, thus causing the Treg/Th17 pregnant women. Additionally, one study reported that the + + imbalance observed in PE (226). Consistent with this, mice placenta was enriched in CD4 HLA-G T cells compared studies have shown that blocking of PD-L1 results in lower to the peripheral compartment, and cases of PE have been + + numbers of Tregs and increased Teﬀ and Th17 populations, associated with reduced levels of the CD4 HLA-G T cell as well as increased fetal resorption and reduced litter size subpopulation in both the decidua and in peripheral blood, (227, 228). Moreover, engagement with PD-L1 and secretion indicating an important role for pregnancy (129). As mentioned of TGF-β promote the development of Tregs by increasing earlier, HLA-G-expressing T cells are also observed in the tumor FoxP3 expression, and reducing Teﬀ cell development (227). The microenvironment promoting a tolerogenic immune milieu, but immunosuppressive function of the PD1 pathway seems to work as with other immunological mechanisms having the same eﬀect by similar mechanisms in cancer and pregnancy, though with during pregnancy and cancer development, a favorable eﬀect is opposite eﬀect in terms of prognosis. Whereas, inhibition of the actually opposite in the two settings. Immune suppression by pathway is desirable for activating the immune response against HLA-G is crucial in terms of a healthy pregnancy, but unwanted cancer cells, activation and high PD-L1 expression is important in a cancer setting where it promotes tumor growth. in terms of promoting a healthy pregnancy. Taken together, it has become increasingly clear that Tregs The DCs are central for activation and diﬀerentiation of T cells are an important player in the complex network of immune by presenting antigen and providing co-stimulatory signaling. cells that secure a healthy pregnancy. Regulatory T cells are Formation of the placenta in early pregnancy is associated with central regulators at the maternal-fetal interphase, as well as in increased number of tolerogenic immature (i)DCs. These cells induction of peripheral tolerance during pregnancy. However, have been shown to produce increased levels of IL-10 and induce it is also evident that the Tregs cannot stand alone. The Treg formation during pregnancy (229–231). Further, Tregs Treg cells regulate and are regulated by a variety of cells and have been shown to induce the formation of anti-inﬂammatory immune modulatory molecules. Their exact role and the precise alternatively activated macrophages (M2), partly by IL-10 (232). mechanism by which they exert their immune regulation needs Moreover, Tregs secrete heme oxygenase-1 (HO-1) that keep to be further elucidated. DCs in an immature state in which they secrete higher amounts of IL-10 that further induce the formation of Tregs (233). In Immunotherapeutic Intervention in turn, these cells secrete IDO and TGF-β and engage with the CTLA-4 receptor on Tregs that together impairs allogen-speciﬁc Pregnancy Complications T cell activity and induce Treg formation, further aﬀecting the Clinical treatments based upon immunomodulating Treg Tregs/Teﬀ balance (234, 235). function in cases of infertility, pregnancy loss and pregnancy Uterine and decidual NK cells play important regulatory complications have not yet been implemented in routine settings. functions for the vascularization and formation of the placenta Regarding the use of Treg measurements as a diagnostic or in early pregnancy (236, 237). Like Tregs, a balance between prognostic marker, Winger and Reed have reported an interesting dim bright cytotoxic CD56 and regulatory CD56 NK cells seems but small study of 54 pregnant women with a history of infertility important for a successful pregnancy. Pregnancy complications and/or pregnancy loss (195). In a new pregnancy, 23 of the such as RPL and PE have also been linked to a reduced women experienced another pregnancy loss in the ﬁrst trimester, bright dim CD56 /CD56 NK cell ratio (238, 239). Tregs might also be and 31 women were still pregnant after 12 weeks of gestation. The + + + important in regulation of the dNK cell phenotype. It has been percentage of CD4 CD25 FoxP3 Tregs in peripheral blood shown that Tregs reduce cytotoxicity of NK cells in an TGF- was signiﬁcantly higher in the still pregnant >12 gestational β-dependent fashion and inhibit the release of IL-15 from DCs week compared with the pregnancy loss group at mean day 49.2 that are important for the generation of dNK cells (240, 241). ± 36.1 of the pregnancy. Based on the results from this pilot Likewise, TGF-β secreted from decidual stroma cells has been study the authors propose that measurements of Tregs may serve dim shown to change the peripheral CD56 toward a decidual- as a biomarker for the assessment of risk of pregnancy loss in bright like CD56 NK cell phenotype (242). It is likely that TGF-β newly pregnant women. Clearly, larger studies are needed to secreted from Tregs will have a similar eﬀect on the NK cell validate this. phenotype. On the contrary, NK cells are also able to contribute In a rat model of pregnancy loss induced by the administration to the Treg homeostasis by reducing Th17 cell responses through of lipopolysaccharide (LPS) resulting in maternal inﬂammation + + the production of IFN-γ and inducing CD25 FoxP3 Treg Renaud et al. showed that pregnancy loss could be prevented development (235, 243). by immunomodulation (244). This was either accomplished + +/hi + Apart from the classical CD4 CD25 FoxP3 T cells by administration of IL-10 or by blockade of TNF-α by described above, other types of Tregs have also been associated a TNF-α inhibitor (Etanercept). As discussed previously, with pregnancy. As brieﬂy addressed in previous sections recent studies especially in mice have shown the importance of the studies have identiﬁed an HLA-G-expressing CD4 T cell presence of Tregs for a successful pregnancy. In one study by population with immunosuppressive functions. The HLA-G Heitmann et al. a targeted depletion of Tregs was performed Frontiers in Immunology | www.frontiersin.org 13 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer using a transgenic mouse model (245). It was observed that distant ﬁelds like pregnancy and cancer have close connections embryo implantation in syngenic matings was defective after and could be highly beneﬁcial (246). This would involve a better Treg depletion. However, it was possible to restore embryo mapping of cytokine networks and e.g., interactions with HLA implantation by the transfer of Tregs into the mating mice. It class Ib molecules in both situations. can be speculated that administration or induction of pregnancy- Investigating the similarities in immunity through the related Tregs resembling engineered T cells used in cancer diﬀerent trimesters in pregnancy and in advanced malignancies treatment could rescue some unsuccessful pregnancies caused has the potential to advance the knowledge of mechanisms by abnormal Tregs function either by aberrant number of involved in Treg function and eventually help to overcome cells or a functional defect. There might also be therapeutic the burden of long-term antigen exposure and immunologic potential in blockage or the administration of speciﬁc cytokines exhaustion. Treatment strategies can be aimed at aspects such or HLA class Ib molecules locally in the female reproductive as invasion, angiogenesis, immune privilege, and malignant tract. In theory, such immunomodulation might be able to proliferation (5). We can take advantage of the knowledge from aﬀect numbers or functionality of regulatory T cell subsets the two diﬀerent ﬁelds of cancer and pregnancy complications beneﬁcial for a successful pregnancy. However, this therapeutic and potentially use it to facilitate the search for novel treatment area clearly needs more studies primarily to clarify the basic strategies in either of them. mechanisms upon which new therapeutic strategies may be Modiﬁcation of the presence of Tregs and the function of these based on. cells have been studied more extensively in relation to cancer then A reason as to why treatment based on immune modulation in the case of pregnancy complications, and treatment strategies is not extensively studied in terms of pregnancy complications targeting immunosuppressive pathways are already established compared to the ﬁeld of cancer immunotherapy, might be that for some cancers. However, more discoveries on Treg regulation the focus on the cause of pregnancy complications such as is essential for the exploitation of these cells both in the ﬁeld PE has been directed toward several diﬀerent factors besides of cancer and reproductive immunology in order to improve immune regulation. immunotherapy and to help prevent pregnancy complications. Similar for both ﬁelds, future research in interactions of Tregs with other cells, molecules responsible for recruitment of Tregs CONCLUSIONS AND PERSPECTIVES into the maternal-fetal interface and tumor site, and intracellular pathways of regulatory signaling in Treg cells, will be highly Many similarities exist in the regulatory immune landscape of valuable. Especially knowledge about the interactions of Tregs the tumor microenvironment and at the feto-maternal interface with other immune cells is needed to provide safe treatment and during pregnancy (Figure 1). While trophoblast cells possess to reduce immune-related side eﬀects (246). both maternal and paternal antigens, cancer is also a kind of a chimera consisting of cells presenting both self and tumor- associated antigens. Furthermore, it seems that the role of AUTHOR CONTRIBUTIONS Tregs in pregnancy and cancer, modulating the host response NJ, GP, and TH participated in the design and draft of the directed toward foreign antigens in the placenta and the manuscript. NJ is the main author of sections dealing with tumor, respectively, may not be very diﬀerent. Keeping this in Tregs in cancer, while GP drafted sections regarding Tregs mind, the immunosuppressive role of Tregs in pregnancy is in reproductive immunology. TH was responsible for overall a physiological process, while the inhibitory role of Tregs in supervision and did the ﬁnal proofreading of the draft. All cancer is pathophysiological, which nevertheless also makes the authors have read and accepted the ﬁnal version of the elaboration of immune modulating capacity in both cases even manuscript. The ﬁgures and the table included in the article more appealing. The apparent role of Tregs in early tolerance are made by the authors (Figure 1: TH and GP, Figures 2, 3: induction is another issue also important in both cancer and GP, Table 1: NJ), and the ﬁgures and the table have not been pregnancy. The early Treg response to embryo implantation is published before. similar to those in a cancer setting with Tregs being activated within the ﬁrst days of implantation and tumor emergence, respectively (5, 198). Most essential in reproduction and cancer FUNDING immunology is the similar mechanisms of escape from host immunosurveillance mediated by Tregs in combination with Support for this work was generously provided by The Region Zealand Health Sciences Research Foundation and Zealand other immune cells and immune factors. Therefore, investigating mechanisms engaging Tregs and their regulation in apparently University Hospital. REFERENCES 2. Waldmann H, Graca L, Cobbold S, Adams E, Tone M, Tone Y. Regulatory T cells and organ transplantation. Semin Immunol. (2004) 16:119–26. 1. Sakaguchi S. Naturally arising Foxp3-expressing CD25+ doi: 10.1016/j.smim.2003.12.007 CD4+ regulatory T cells in immunological tolerance to self 3. Wahl SM, Vázquez N, Chen W. Regulatory T cells and transcription factors: and non-self. Nat Immunol. (2005) 6:345–52. doi: 10.1038/n gatekeepers in allergic inﬂammation. Curr Opin Immunol. (2004) 16:768–74. i1178 doi: 10.1016/j.coi.2004.09.006 Frontiers in Immunology | www.frontiersin.org 14 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer 4. Munn DH, Mellor AL. The tumor-draining lymph node as xenogeneic response. Xenotransplantation. (2010) 17:121–30. an immune-privileged site. Immunol Rev. (2006) 213:146–58. doi: 10.1111/j.1399-3089.2010.00571.x doi: 10.1111/j.1600-065X.2006.00444.x 26. Liu W, Putnam AL, Xu-yu Z, Szot GL, Lee MR, Zhu S, et al. 5. Holtan SG, Creedon DJ, Haluska P, Markovic SN. Cancer and pregnancy: CD127 expression inversely correlates with FoxP3 and suppressive parallels in growth, invasion, and immune modulation and implications function of human CD4+ T reg cells. J Exp Med. (2006) 203:1701–11. for cancer therapeutic agents. Mayo Clin Proc. (2009) 84:985–1000. doi: 10.1084/jem.20060772 doi: 10.1016/S0025-6196(11)60669-1 27. Klein S, Kretz CC, Krammer PH, Kuhn A. CD127 low/and FoxP3 6. Hviid TVF. HLA-G in human reproduction: aspects of genetics, function expression levels characterize diﬀerent regulatory T-cell populations and pregnancy complications. Hum Reprod Update. (2006) 12:209–232. in human peripheral blood. J Invest Dermatol. (2010) 130:492–9. doi: 10.1093/humupd/dmi048 doi: 10.1038/jid.2009.313 7. Persson G, Melsted WN, Nilsson LL, Hviid TVF. HLA class Ib in 28. Chien C-H, Chiang BL. Regulatory T cells induced by B cells: a pregnancy and pregnancy-related disorders. Immunogenetics. (2017) 69:581– novel subpopulation of regulatory T cells. J Biomed Sci. (2017) 24:86. 95. doi: 10.1007/s00251-017-0988-4 doi: 10.1186/s12929-017-0391-3 8. Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell 29. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Res. (2017) 27:109–118. doi: 10.1038/cr.2016.151 Regulatory T cell lineage speciﬁcation by the forkhead transcription factor 9. Andersen MH. Immune regulation by self-recognition: novel possibilities Foxp3. Immunity. (2005) 22:329–41. doi: 10.1016/j.immuni.2005.01.016 for anticancer immunotherapy. J Natl Cancer Inst. (2015) 107:djv154. 30. Tanchot C, Terme M, Pere H, Tran T, Benhamouda N, Strioga M, doi: 10.1093/jnci/djv154 et al. Tumor-inﬁltrating regulatory T cells: phenotype, role, mechanism 10. Guerin LR, Prins JR, Robertson SA. Regulatory T-cells and immune tolerance of expansion in situ and clinical signiﬁcance. Cancer Microenviron. (2013) in pregnancy: a new target for infertility treatment? Hum Reprod Update. 6:147–57. doi: 10.1007/s12307-012-0122-y (2009) 15:517–35. doi: 10.1093/humupd/dmp004 31. Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment 11. Yu Y, Ma X, Gong R, Zhu J, Wei L, Yao J. Recent advances in CD8+regulatory and cancer progression: role and therapeutic targeting. Vaccines. (2016) 4:28. T cell research. Oncol Lett. (2018) 15:8187–94. doi: 10.3892/ol.2018.8378 doi: 10.3390/vaccines4030028 12. Zhang S, Wu M, Wang F. Immune regulation by CD8+ Treg cells: novel 32. Weiner HL. Induction and mechanism of action of transforming growth possibilities for anticancer immunotherapy. Cell Mol Immunol. (2018) factor-beta-secreting Th3 regulatory cells. Immunol Rev. (2001) 182:207–14. 15:805–7. doi: 10.1038/cmi.2018.170 doi: 10.1034/j.1600-065X.2001.1820117.x 13. Seddiki N, Santner-Nanan B, Tangye SG, Alexander SI, Solomon M, Lee S, 33. Zeng H, Zhang R, Jin B, Chen L. Type 1 regulatory T cells: a new mechanism et al. Persistence of naive CD45RA+ regulatoryTcells in adult life. Blood. of peripheral immune tolerance. Cell Mol Immunol. (2015) 12:566–71. (2006) 107:2830–2838. doi: 10.1182/blood-2005-06-2403.Supported doi: 10.1038/cmi.2015.44 14. Gershon RK, Cohen P, Hencin R, Liebhaber SA. Suppressor T cells. J 34. Jonuleit H, Schmitt E. The regulatory T cell family: distinct Immunol. (1972) 108:586–90. subsets and their interrelations. J Immunol. (2003) 171:6323–7. 15. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self- doi: 10.4049/jimmunol.171.12.6323 tolerance maintained by activated T cells expressing IL-2 receptor alpha- 35. Hoeppli RE, MacDonald KG, Levings MK, Cook L. How antigen speciﬁcity chains (CD25). Breakdown of a single mechanism of self-tolerance causes directs regulatory T-cell function: self, foreign and engineered speciﬁcity. various autoimmune diseases. J Immunol. (1995) 155:1151–64. HLA. (2016) 88:3–13. doi: 10.1111/tan.12822 16. Thornton AM, Shevach EM. CD4 + CD25 + immunoregulatory T Cells 36. Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey- Suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 Bucktrout S, et al. Neuropilin-1 distinguishes natural and inducible production. J Exp Med. (1998) 188:287–96. doi: 10.1084/jem.188.2.287 regulatory T cells among regulatory T cell subsets in vivo. J Exp Med. (2012) 17. Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, 209:1713–22. doi: 10.1084/jem.20120822 et al. Immunologic self-tolerance maintained by CD25+CD4+naturally 37. Shevach EM, Thornton AM. tTregs, pTregs, and iTregs: similarities and anergic and suppressive T cells: Induction of autoimmune disease by diﬀerences. Immunol Rev. (2014) 259:88–102. doi: 10.1111/imr.12160 breaking their anergic/suppressive state. Int Immunol. (1998) 10:1969–80. 38. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, doi: 10.1093/intimm/10.12.1969 Belkaid Y, et al. Expression of Helios, an Ikaros transcription factor 18. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. family member, diﬀerentiates thymic-derived from peripherally Identiﬁcation and functional characterization of human Cd4 + Cd25 + T induced Foxp3 + T regulatory cells. J Immunol. (2010) 184:3433–1. cells with regulatory properties isolated from peripheral blood. J Exp Med. doi: 10.4049/jimmunol.0904028 (2001) 193:1285–94. doi: 10.1084/jem.193.11.1285 39. Lin X, Chen M, Liu Y, Guo Z, He X, Brand D, et al. Advances in 19. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, David A, et al. distinguishing natural from induced Foxp3+ regulatory T cells. Int J. Human CD4+CD25+ cells : a naturally occurring population of regulatory (2013) 6:116–23. Retrieved from: http://www.ijcep.com/. T cells. Blood. (2013) 98:2736–44. doi: 10.1182/blood.V98.9.2736 40. Dunussi-Joannopoulos K, LaBranche TP, Ryan MS, Medley QG, Keegan 20. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo SP, Collins M, et al. Enhanced GITR/GITRL interactions augment IL-27 isolation and characterization of Cd4 + Cd25 + T cells with regulatory expression and induce IL-10-producing Tr-1 like cells. Eur J Immunol. (2012) properties from human blood. J Exp Med. (2001) 193:1303–10. 42:1393–404. doi: 10.1002/eji.201142162 doi: 10.1084/jem.193.11.1303 41. Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y, Owen DL, et al. 21. Baecher-Allan C, Brown JA, Freeman GJ, Haﬂer DA. CD4+CD25high Tumor necrosis factor receptor superfamily costimulation couples T cell regulatory cells in human peripheral blood. J Immunol. (2001) 167:1245–53. receptor signal strength to thymic regulatory T cell diﬀerentiation. Nat doi: 10.4049/jimmunol.167.3.1245 Immunol. (2014) 15:473–81. doi: 10.1038/nature08728.An 22. Hori S. Control of regulatory T cell development by the transcription factor 42. Ronchetti S, Ricci E, Petrillo MG, Cari L, Migliorati G, Nocentini G, et al. Foxp3. Science. (2003) 299:1057–61. doi: 10.1126/science.1079490 Glucocorticoid-induced tumour necrosis factor receptor-related protein: 23. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for a key marker of functional regulatory T cells. J Immunol Res. (2015) Scurﬁn in CD4+CD25+T regulatory cells. J Immunol. (2003) 198:993–8. 2015:171520. doi: 10.1155/2015/171520 doi: 10.1038/ni909 43. Andrews LP, Marciscano AE, Drake CG, Vignali DAA. LAG3 (CD223) 24. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development as a cancer immunotherapy target. Immunol Rev. (2017) 276:80–96. and function of CD4+CD25+ regulatory T cells. Nat Immunol. (2003) doi: 10.1111/imr.12519 4:330–6. doi: 10.1038/ni904 44. Antonioli L, Pacher P, Vizi ES, Haskó G. CD39 and CD73 in 25. Sun L, Yi S, O’Connell PJ. Foxp3 regulates human natural immunity and inﬂammation. Trends Mol Med. (2013) 19:355–67. CD4+CD25+ regulatory T-cell-mediated suppression of doi: 10.1016/j.molmed.2013.03.005 Frontiers in Immunology | www.frontiersin.org 15 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer 45. Mandapathil M, Szczepanski MJ, Szajnik M, Ren J, Jackson EK, Johnson 64. Pankratz S, Ruck T, Meuth SG, Wiendl H. CD4+HLA-G+ regulatory T JT, et al. Adenosine and prostaglandin e2 cooperate in the suppression of cells: molecular signature and pathophysiological relevance. Hum Immunol. immune responses mediated by adaptive regulatory T cells. J Biol Chem. (2016) 77:727–33. doi: 10.1016/j.humimm.2016.01.016 (2010) 285:27571–80. doi: 10.1074/jbc.M110.127100 65. Fridman WH, Pagès F, Sauts-Fridman C, Galon J. The immune contexture 46. Campbell DJ, Koch MA. Phenotypical and functional specialization in human tumours: impact on clinical outcome. Nat Rev Cancer. (2012) of FOXP3+ regulatory T cells. Nat Rev Immunol. (2011) 11:119–30. 12:298–306. doi: 10.1038/nrc3245 doi: 10.1038/nri2916 66. Whiteside T. The role of regulatory T cells in cancer immunology. 47. Suto A, Nakajima H, Ikeda K, Kubo S, Nakayama T, Taniguchi M, ImmunoTargets Ther. (2015) 4:159–71. doi: 10.2147/ITT.S55415 et al. CD4+CD25+T-cell development is regulated by at least 2 distinct 67. Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-inﬁltrating mechanisms. Blood. (2002) 99:555–60. doi: 10.1182/blood.V99.2.555 FoxP3+regulatory T cells in cancers: a systematic review and meta-analysis. 48. Pacholczyk R, Kraj P, Ignatowicz L. Peptide speciﬁcity of thymic Sci Rep. (2015) 5:15179. doi: 10.1038/srep15179 selection of CD4+CD25+ T cells. J Immunol. (2002) 168:613–20. 68. Jacobs JFM, Nierkens S, Figdor CG, de Vries IJM, Adema GJ. Regulatory doi: 10.4049/jimmunol.168.2.613 T cells in melanoma: The ﬁnal hurdle towards eﬀective immunotherapy? 49. Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, Lancet Oncol. (2012) 13:e32–42. doi: 10.1016/S1470-2045(11)70155-3 et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an 69. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. agonist self-peptide. Nat Immunol. (2001) 2:301–6. doi: 10.1038/86302 Speciﬁc recruitment of regulatory T cells in ovarian carcinoma fosters 50. Thornton AM, Shevach EM. Suppressor eﬀector function of CD4+CD25+ immune privilege and predicts reduced survival. Nat Med. (2004) 10:942–9. Immunoregulatory T cells is antigen nonspeciﬁc. J Immunol. (2000) doi: 10.1038/nm1093 164:183–90. doi: 10.4049/jimmunol.164.1.183 70. Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, 51. Kosten IJ, Rustemeyer T. Generation, subsets and functions of inducible Korangy F. Increased Populations of Regulatory T cells in peripheral blood regulatory T cells. Antiinﬂamm Antiallergy Agents Med Chem. (2015) of patients with hepatocellular carcinoma. Cancer Res. (2005) 65:2457–64. 13:139–53. doi: 10.2174/1871523013666141126100019 doi: 10.1158/0008-5472.CAN-04-3232 52. Passerini L, Di Nunzio S, Gregori S, Gambineri E, Cecconi M, Seidel MG, 71. Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H. Increased et al. Functional type 1 regulatory T cells develop regardless of FOXP3 populations of regulatory T cells in peripheral blood and tumor-inﬁltrating mutations in patients with IPEX syndrome. Eur J Immunol. (2011) 41:1120– lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res. 31. doi: 10.1002/eji.201040909 (2003) 9:4404–8. Retrieved from: http://clincancerres.aacrjournals.org. 53. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion 72. Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Endl E, et al. Reduced of peripheral CD4 CD25 naive T cells to CD4 CD25 regulatory T cells by frequencies and suppressive function of CD4+ CD25 hi regulatory T cells in TGF-induction of transcription factor Foxp3. J Exp Med J Exp Med. (2003) patients with chronic lymphocytic leukemia after therapy with ﬂudarabine. 198:1875–86. doi: 10.1084/jem.20030152 Blood. (2005) 106:2018–25. doi: 10.1182/blood-2005-02-0642.Supported 54. Bacchetta R, Sartirana C, Levings MK, Bordignon C, Narula S, 73. Bohling SD, Allison KH. Immunosuppressive regulatory T cells are Roncarolo MG. Growth and expansion of human T regulatory associated with aggressive breast cancer phenotypes: a potential therapeutic type 1 cells are independent from TCR activation but require target. Mod Pathol. (2008) 21:1527–32. doi: 10.1038/modpathol.2008.160 exogenous cytokines. Eur J Immunol. (2002) 32:2237–45. 74. Kono K, Kawaida H, Takahashi A, Sugai H, Mimura K, Miyagawa N, et al. doi: 10.1002/1521-4141(200208)32:8<2237::AID-IMMU2237>3.0.CO;2-2 CD4(+)CD25high regulatory T cells increase with tumor stage in patients 55. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, et al. with gastric and esophageal cancers. Cancer Immunol Immunother. (2006) A CD4+T-cell subset inhibits antigen-speciﬁc T-cell responses and prevents 55:1064–71. doi: 10.1007/s00262-005-0092-8 colitis. Nature. (1997) 389:737–42. doi: 10.1038/39614 75. Liyanage UK, Moore TT, Joo H-GH-G, Tanaka Y, Herrmann V, 56. Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt Doherty G, et al. Prevalence of regulatory T cells is increased in R, Roncarolo MG. IFN-a and IL-10 induce the diﬀerentiation of peripheral blood and tumor microenvironment of patients with human Type 1 T regulatory cells. J Immunol. (2001) 166:5530–9. pancreas or breast adenocarcinoma. J Immunol. (2002) 169:2756–61. doi: 10.4049/jimmunol.166.9.5530 doi: 10.4049/jimmunol.169.5.2756 57. Levings MK, Bacchetta R, Schulz U, Roncarolo MG. The role of IL-10 and 76. Milne K, Köbel M, Kalloger SE, Barnes RO, Gao D, Gilks CB, et al. Systematic TGF-beta in the diﬀerentiation and eﬀector function of T regulatory cells. analysis of immune inﬁltrates in high-grade serous ovarian cancer reveals Int Arch Allergy Immunol. (2002) 129:263–76. doi: 10.1159/000067596 CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS ONE. (2009) 58. Chen Y, Kuchroo V, Inobe J, Haﬂer D, Weiner H. Regulatory T cell clones 4:e6412. doi: 10.1371/journal.pone.0006412 induced by oral tolerance: suppression of autoimmune encephalomyelitis. 77. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon Science. (1994) 265:1237–40. doi: 10.1126/science.7520605 S, Arﬁ V, et al. Regulatory T cells recruited through CCL22/CCR4 are 59. Weiner HL. The mucosal milieu creates tolerogenic dendritic cells and TR1 selectively activated in lymphoid inﬁltrates surrounding primary breast and TH3 regulatory cells. Nat Immunol. (2001) 2:671–2. doi: 10.1038/90604 tumors and lead to an adverse clinical outcome. Cancer Res. (2009) 69:2000– 60. Fukaura H, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Haﬂer 9. doi: 10.1158/0008-5472.CAN-08-2360 DA. Induction of circulating myelin basic protein and proteolipid protein- 78. Demir L, Yigit S, Ellidokuz H, Erten C, Somali I, Kucukzeybek Y, et al. speciﬁc transforming growth factor-beta1-secreting Th3 T cells by oral Predictive and prognostic factors in locally advanced breast cancer: eﬀect administration of myelin in multiple sclerosis patients. J Clin Invest. (1996) of intratumoral FOXP3+ Tregs. Clin Exp Metastasis. (2013) 30:1047–62. 98:70–7. doi: 10.1172/JCI118779 doi: 10.1007/s10585-013-9602-9 61. Feger U, Tolosa E, Huang Y-H, Waschbisch A, Biedermann T, Melms A, 79. Sun S, Fei X, Mao Y, Wang X, Garﬁeld DH, Huang O, et al. PD- et al. HLA-G expression deﬁnes a novel regulatory T-cell subset present in 1+ immune cell inﬁltration inversely correlates with survival of operable human peripheral blood and sites of inﬂammation. Blood. (2007) 110:568– breast cancer patients. Cancer Immunol Immunother. (2014) 63:395–406. 77. doi: 10.1182/blood-2006-11-057125 doi: 10.1007/s00262-014-1519-x 62. Pankratz S, Bittner S, Herrmann AM, Schuhmann MK, Ruck T, Meuth 80. West NR, Kost SE, Martin SD, Milne K, Deleeuw RJ, Nelson BH, et al. SG, et al. Human CD4 + HLA-G + regulatory T cells are potent Tumour-inﬁltrating FOXP3 + lymphocytes are associated with cytotoxic suppressors of graft-versus-host disease in vivo. FASEB J. (2014) 28:3435–45. immune responses and good clinical outcome in oestrogen receptor-negative doi: 10.1096/fj.14-251074 breast cancer. Br J Cancer. (2013) 108:155–62. doi: 10.1038/bjc.2012.524 63. Huang YH, Zozulya AL, Weidenfeller C, Schwab N, Wiendl H. T cell 81. Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, et al. Quantiﬁcation suppression by naturally occurring HLA-G-expressing regulatory CD4 + of regulatory T cells enables the identiﬁcation of high-risk breast cancer T cells is IL-10-dependent and reversible. J Leukoc Biol. (2009) 86:273–81. patients and those at risk of late relapse. J Clin Oncol. (2006) 24:5373–80. doi: 10.1189/jlb.1008649 doi: 10.1200/JCO.2006.05.9584 Frontiers in Immunology | www.frontiersin.org 16 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer 82. Liu S, Foulkes WD, Leung S, Gao D, Lau S, Kos Z, et al. Prognostic ovarian carcinoma patients. Proc Natl Acad Sci USA. (2003) 100:4712–7. signiﬁcance of FOXP3+ tumor-inﬁltrating lymphocytes in breast doi: 10.1073/pnas.0830997100 cancer depends on estrogen receptor and human epidermal growth 99. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, factor receptor-2 expression status and concurrent cytotoxic T-cell Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T inﬁltration. Breast Cancer Res. (2014) 16:432. doi: 10.1186/s13058-01 cell function. Science. (2008) 322:271–5. doi: 10.1126/science.11 4-0432-8 60062 83. Lee S, Cho EY, Park YH, Ahn JS, Im YH. Prognostic impact of FOXP3 100. Onodera T, Jang MH, Guo Z, Yamasaki M, Hirata T, Bai Z, et al. Constitutive expression in triple-negative breast cancer. Acta Oncol. (2013) 52:73–81. expression of IDO by dendritic cells of mesenteric lymph nodes: functional doi: 10.3109/0284186X.2012.731520 involvement of the CTLA-4/B7 and CCL22/CCR4 interactions. J Immunol. 84. Liu Z, Li M, Jiang Z, Wang X. A comprehensive immunologic (2009) 183:5608–14. doi: 10.4049/jimmunol.0804116 portrait of triple-negative breast cancer. Transl Oncol. (2018) 11:311–29. 101. Godin-Ethier J, Hanaﬁ LA, Piccirillo CA, Lapointe R. Indoleamine doi: 10.1016/j.tranon.2018.01.011 2,3-dioxygenase expression in human cancers: clinical and 85. Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, et al. immunologic perspectives. Clin Cancer Res. (2011) 17:6985–91. High frequency of tumor-inﬁltrating FOXP3 + regulatory T cells predicts doi: 10.1158/1078-0432.CCR-11-1331 improved survival in mismatch repair-proﬁcient colorectal cancer patients. 102. Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: Int J Cancer. (2010) 2643:2635–43. doi: 10.1002/ijc.24989 beyond IDO and tryptophan depletion. Cancer Res. (2012) 72:5435–40. 86. Chang LY, Lin YC, Mahalingam J, Huang CT, Chen TW, Kang CW, et al. doi: 10.1158/0008-5472.CAN-12-0569 Tumor-derived chemokine CCL5 enhances TGF- -mediated killing of CD8+ 103. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of T cells in colon cancer by T-regulatory cells. Cancer Res. (2012) 72:1092–102. lupus-like autoimmune diseases by disruption of the PD-1 gene encoding doi: 10.1158/0008-5472.CAN-11-2493 an ITIM motif-carrying immunoreceptor. Immunity. (1999) 11:141–51. 87. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ doi: 10.1016/S1074-7613(00)80089-8 regulatory T cells increases during the progression of pancreatic ductal 104. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. adenocarcinoma and its premalignant lesions. Clin Cancer Res. (2006) Engagement of the Pd-1 immunoinhibitory receptor by a novel B7 family 12:5423–34. doi: 10.1158/1078-0432.CCR-06-0369 member leads to negative regulation of lymphocyte activation. J Exp Med. 88. Miracco C, Mourmouras V, Biagioli M, Rubegni P, Mannucci S, Monciatti (2000) 192:1027–34. doi: 10.1084/jem.192.7.1027 I, et al. Utility of tumour-inﬁltrating CD25+FOXP3+ regulatory T cell 105. Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread evaluation in predicting local recurrence in vertical growth phase cutaneous of poorly immunogenic tumor cells by enhanced recruitment of eﬀector T melanoma. Oncol Rep. (2007) 18:1115–22. doi: 10.3892/or.18.5.1115 cells. Int Immunol. (2005) 17:133–44. doi: 10.1093/intimm/dxh194 89. Ladányi A, Mohos A, Somlai B, Liszkay G, Gilde K, Fejos Z, et al. 106. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation FOXP3+cell density in primary tumor has no prognostic impact in patients of CD25+CD4+ regulatory T cells through GITR breaks immunological with cutaneous malignant melanoma. Pathol Oncol Res. (2010) 16:303–9. self-tolerance. Nat Immunol. (2002) 3:135–42. doi: 10.1038/ni759 doi: 10.1007/s12253-010-9254-x 107. Stephens GL, Collins M, Shevach EM, Carreno BM, McHugh RS, 90. Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge Young DA, et al. Engagement of Glucocorticoid-induced TNFR family- T, et al. FOXP3+ Regulatory T cells aﬀect the development and related receptor on eﬀector T cells by its ligand mediates resistance to progression of hepatocarcinogenesis. Clin Cancer Res. (2007) 13:902–11. suppression by CD4+CD25+ T cells. J Immunol. (2014) 173:5008–20. doi: 10.1158/1078-0432.CCR-06-2363 doi: 10.4049/jimmunol.173.8.5008 91. Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay NEH, et al. 108. Hashiguchi S, Nishioka T, Takahashi T, Kanamaru F, Youngnak P. Prognostic value of tumor-inﬁltrating CD4+ T-cell subpopulations T cells + regulatory CD4 + CD25 TNF receptor in both conventional in head and neck cancers. Clin Cancer Res. (2006) 12:465–72. and costimulation via Glucocorticoid-induced Sakaguchi, Isao doi: 10.1158/1078-0432.CCR-05-1886 Ishikawa and Miyuki Azuma. J Immunol Ref. (2004) 172:7306–7314. 92. Drennan S, Staﬀord ND, Greenman J, Green VL. Increased frequency and doi: 10.4049/jimmunol.172.12.7306 suppressive activity of CD127 low/- Tregs in the peripheral circulation of 109. Krausz LT, Fischer-Fodor E, Majorl ZZ, Fetica B. Gitr-expressing patients with head and neck squamous cell carcinoma are associated with regulatory T-cell subsets are increased in tumor-positive lymph advanced stage and nodal involvement. Immunology. (2013) 140:335–43. nodes from advanced breast cancer patients as compared to tumor- doi: 10.1111/imm.12144 negative lymph nodes. Int J Immunopathol Pharmacol. (2012) 25:59–66. 93. Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. doi: 10.1177/039463201202500108 Correlation of high numbers of intratumoral FOXP3+ regulatory T 110. Silva JS, Tiezzi DG, Benevides L, Andrade JM, Marana HRC, Cardoso CRB. cells with improved survival in germinal center-like diﬀuse large B- Enrichment of regulatory T cells in invasive breast tumor correlates with cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. the upregulation of IL-17A expression and invasiveness of the tumor. Eur Haematologica. (2008) 93:193–200. doi: 10.3324/haematol.11702 J Immunol. (2013) 43:1518–28. doi: 10.1002/eji.201242951 94. Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G, 111. Ephrem A, Epstein AL, Stephens GL, Thornton AM, Glass D, Shevach EM. et al. High numbers of tumor-inﬁltrating FOXP3-positive regulatory T cells Modulation of Treg cells/T eﬀector function by GITR signaling is context- are associated with improved overall survival in follicular lymphoma. Blood. dependent. Eur J Immunol. (2013) 43:2421–9. doi: 10.1002/eji.201343451 (2006) 108:2957–64. doi: 10.1182/blood-2006-04-018218 112. Belkaid Y, Piccirillo CA, Mendez S. CD4+ CD25+ regulatory T cells control 95. Álvaro T, Lejeune M, Salvadó MT, Bosch R, García JF, Jaén J, et al. Leishmania major persistence and immunity. Nature. (2002) 420:633–7. Outcome in Hodgkin’s lymphoma can be predicted from the presence of doi: 10.1038/nature01199.1 accompanying cytotoxic and regulatory T cells. Clin Cancer Res. (2005) 113. Asseman C, Mauze S, Leach MW, Coﬀman RL, Powrie F. An essential role 11:1467–73. doi: 10.1158/1078-0432.CCR-04-1869 for interleukin 10 in the function of regulatory T cells that inhibit intestinal 96. Schreck S, Friebel D, Buettner M, Distel L, Grabenbauer G, Young LS, inﬂammation. J Exp Med. (1999) 190:995–1004. doi: 10.1084/jem.190.7.995 et al. Prognostic impact of tumour-inﬁltrating Th2 and regulatory T 114. Loser K, Apelt J, Voskort M, Mohaupt M, Balkow S, Schwarz T, et al. IL- cells in classical Hodgkin lymphoma. Hematol Oncol. (2009) 27:31–9. 10 controls ultraviolet-induced carcinogenesis in mice. J Immunol. (2007) doi: 10.1002/hon.878 179:365–71. doi: 10.4049/jimmunol.179.1.365 97. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor 115. Landskron G, la Fuente MD, Thuwajit P, Thuwajit C, Hermoso MA. Chronic immunity by CTLA-4 blockade. Adv Sci. (2010) 271:1734–6. Inﬂammation and Cytokines in the Tumor Microenvironment. J Immunol doi: 10.1126/science.271.5256.1734 Res. (2014) 2014:149185. doi: 10.1155/2014/149185 98. Hodi FS, Mihm MC, Soiﬀer RJ, Haluska FG, Butler M, Seiden MV, 116. Surh CD, Bayer AL, de la Barrera A, Lee JY, Malek TR. A function for IL-7R et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 for CD4+CD25+Foxp3+ T regulatory cells. J Immunol. (2014) 181:225–34. antibody blockade in previously vaccinated metastatic melanoma and doi: 10.4049/jimmunol.181.1.225 Frontiers in Immunology | www.frontiersin.org 17 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer 117. Hoeppli RE, Wu D, Cook L, Levings MK. The environment of regulatory 136. Wang HY, Peng G, Guo Z, Shevach EM, Wang RF. Recognition of T cell biology: cytokines, metabolites, and the microbiome. Front Immunol. a New ARTC1 peptide ligand uniquely expressed in tumor cells by (2015) 6:61. doi: 10.3389/ﬁmmu.2015.00061 antigen-speciﬁc CD4+ regulatory T cells. J Immunol. (2005) 174:2661–70. 118. Carosella ED, Rouas-Freiss N, Le Roux DT, Moreau P, LeMaoult J. HLA-G. doi: 10.4049/jimmunol.174.5.2661 An Immune Checkpoint Molecule. Adv Immunol. 1st ed. Paris: Elsevier Inc. 137. Vence L, Palucka AK, Fay JW, Ito T, Liu Y-J, Banchereau J, et al. (2015) 127:33–144. doi: 10.1016/bs.ai.2015.04.001 Circulating tumor antigen-speciﬁc regulatory T cells in patients with 119. Vangangelt KMH, van Pelt GW, Engels CC, Putter H, Liefers GJ, Smit metastatic melanoma. Proc Natl Acad Sci USA. (2007) 104:20884–9. VTHBM, et al. Prognostic value of tumor–stroma ratio combined with the doi: 10.1073/pnas.0710557105 immune status of tumors in invasive breast carcinoma. Breast Cancer Res 138. Bonertz A, Weitz J, Pietsch DK, Rahbari NN, Schlude C, Ge Y, et al. Treat. (2017) 168:601–12. doi: 10.1007/s10549-017-4617-6 Antigen-speciﬁc Tregs control T cell responses against a limited repertoire of 120. de Kruijf EM, Sajet A, van Nes JGH, Natanov R, Putter H, Smit VTHBM, tumor antigens in patients with colorectal carcinoma. J Clin Investig. (2009) et al. HLA-E and HLA-G expression in classical HLA class I-negative tumors 119:3311–21. doi: 10.1172/JCI39608.tumor is of prognostic value for clinical outcome of early breast cancer patients. J 139. Betts G, Jones E, Junaid S, El-Shanawany T, Scurr M, Mizen P, et al. Immunol. (2010) 185:7452–59. doi: 10.4049/jimmunol.1002629 Suppression of tumour-speciﬁc CD4 + T cells by regulatory T cells 121. Ramos CS, Gonçalves AS, Marinho LC, Gomes Avelino MA, Saddi VA, Lopes is associated with progression of human colorectal cancer. Gut. (2012) AC, et al. Analysis of HLA-G gene polymorphism and protein expression 61:1163–71. doi: 10.1136/gutjnl-2011-300970 in invasive breast ductal carcinoma. Hum Immunol. (2014) 75:667–72. 140. Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, et al. Visualizing doi: 10.1016/j.humimm.2014.04.005 regulatory T cell control of autoimmune responses in nonobese diabetic 122. Ueshima C, Kataoka TR, Hirata M, Furuhata A, Suzuki E, Toi M, et al. mice. Nat Immunol. (2006) 7:83–92. doi: 10.1038/ni1289 The killer cell Ig-like receptor 2DL4 expression in human mast cells and 141. Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. CD25 + CD4 its potential role in breast cancer invasion. Cancer Immunol Res. (2015) + T cells, expanded with dendritic cells presenting a single autoantigenic 3:871–80. doi: 10.1158/2326-6066.CIR-14-0199 peptide, suppress autoimmune diabetes. J Exp Med. (2004) 199:1467–77. 123. da Silva GBRF, Silva TGA, Duarte RA, Neto NL, Carrara HHA, Donadi EA, doi: 10.1084/jem.20040180 et al. Expression of the classical and nonclassical HLA molecules in breast 142. Nishikawa H, Kato T, Tanida K, Hiasa A, Tawara I, Ikeda H, et al. CD4+ cancer. Int J Breast Cancer. (2013) 2013:250435. doi: 10.1155/2013/250435 CD25+ T cells responding to serologically deﬁned autoantigens suppress 124. Du L, Xiao X, Wang C, Zhang X, Zheng N, Wang L, et al. Human leukocyte antitumor immune responses. Proc Natl Acad Sci USA. (2003) 100:10902–6. antigen-G is closely associated with tumor immune escape in gastric cancer doi: 10.1073/pnas.1834479100 by increasing local regulatory T cells. Cancer Sci. (2011) 102:1272–80. 143. Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, et al. doi: 10.1111/j.1349-7006.2011.01951.x Aire-dependent thymic development of tumor-associated regulatory T cells. 125. Adrián Cabestré F, Moreau P, Riteau B, Ibrahim EC, Le Danﬀ Science. (2013) 339:1219–24. doi: 10.1126/science.1233913 C, Dausset J, et al. HLA-G expression in human melanoma cells: 144. Gnjatic S, Bronte V, Brunet LR, Butler MO, Disis ML, Galon J, et al. Protection from NK cytolysis. J Reprod Immunol. (1999) 43:183–93. Identifying baseline immune-related biomarkers to predict clinical doi: 10.1016/S0165-0378(99)00037-6 outcome of immunotherapy. J Immunother Cancer. (2017) 5:44. 126. Melsted WN, Johansen LL, Lock-Andersen J, Behrendt N, Eriksen JO, Bzorek doi: 10.1186/s40425-017-0243-4 M, et al. HLA class Ia and Ib molecules and FOXP3+ TILs in relation to the 145. Fellner C. Ipilimumab (yervoy) prolongs survival in advanced melanoma: prognosis of malignant melanoma patients. Clin Immunol. (2017) 183:191–7. serious side eﬀects and a hefty price tag may limit its use. P T. (2012) doi: 10.1016/j.clim.2017.09.004 37:503–30. Retrieved from: https://www.ptcommunity.com/. 127. Melsted WN, Matzen SH, Andersen MH, Hviid TVF. The choriocarcinoma 146. Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. cell line JEG-3 upregulates regulatory T cell phenotypes and modulates pro- Durable clinical beneﬁt with nivolumab plus ipilimumab in DNA mismatch inﬂammatory cytokines through HLA-G. Cell Immunol. (2017) 324:14–23. repair–deﬁcient/microsatellite instability–high metastatic colorectal cancer. doi: 10.1016/j.cellimm.2017.11.008 J Clin Oncol. (2018) 36:773–9. doi: 10.1200/JCO.2017.76.9901 128. Wang C, Chen J, Zhang Q, Li W, Zhang S, Xu Y, et al. Elimination of CD4 low 147. Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok HLA-G+ T cells overcomes castration- resistance in prostate cancer therapy. JD, Schmidt H, et al. Prolonged survival in stage III melanoma (2018) Cell Res. (2018) 28:1103–17. doi: 10.1038/s41422-018-0089-4 with ipilimumab adjuvant therapy. N Engl J Med. (2016) 375:1845–55. 129. Hsu P, Santner-Nanan B, Joung S, Peek MJ, Nanan R. Expansion of doi: 10.1056/NEJMoa1611299 CD4+HLA-G+T cell in human pregnancy is impaired in pre-eclampsia. Am 148. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. J Reprod Immunol. (2014) 71:217–28. doi: 10.1111/aji.12195 Improved survival with ipilimumab in patients with metastatic melanoma. N 130. Darrasse-Jèze G, Podsypanina K. How numbers, nature, and immune Engl J Med. (2010) 363:711–23. doi: 10.1056/NEJMoa1003466 status of Foxp3+regulatory T-cells shape the early immunological events in 149. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar tumor development. Front Immunol. (2013) 4:292. doi: 10.3389/ﬁmmu.2013. B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib 00292 in advanced renal-cell carcinoma. N Engl J Med. (2018) 378:1277–90. 131. Darrasse-Jèze G, Bergot A, Durgeau A, Billiard F, Salomon BL, Cohen JL, doi: 10.1056/NEJMoa1712126 et al. Tumor emergence is sensed by self-speciﬁc CD44hi memory Tregs that 150. Fumet J-D, Isambert N, Hervieu A, Zanetta S, Guion J-F, Hennequin A, create a dominant tolerogenic environment for tumors in mice. J Clin Invest. et al. Phase Ib/II trial evaluating the safety, tolerability and immunological (2009) 119:2648–62. doi: 10.1172/JCI36628 activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti- 132. Bhatnagar RM, Zabriskie JB, Rausen AR. Cellular immune responses to CTLA-4) combined with FOLFOX in patients with metastatic colorectal methylcholanthrene-induced ﬁbrosarcoma in BALB/c mice. J Exp Med. cancer. ESMO Open. (2018) 3:e000375. doi: 10.1136/esmoopen-2018-0 (1975) 142:839–55. doi: 10.1084/jem.142.4.839 00375 133. Savage PA, Leventhal DS, Malchow S. Shaping the repertoire of tumor- 151. Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta inﬁltrating eﬀector and regulatory T cells. Immunol Rev. (2014) 259:245–58. A, et al. Safety and antitumour activity of durvalumab plus tremelimumab doi: 10.1111/imr.12166 in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 134. Lu Y-C, Robbins PF. Cancer immunotherapy targeting neoantigens. Semin (2016) 17:299–308. doi: 10.1016/S1470-2045(15)00544-6 Immunol. (2016) 28:22–7. doi: 10.1016/j.smim.2015.11.002 152. Martínez P, del Campo JM. Pembrolizumab in recurrent advanced 135. Wang HY, Lee DA, Peng G, Guo Z, Li Y, Kiniwa Y, et al. cervical squamous carcinoma. Immunotherapy. (2017) 9:467–70. Tumor-speciﬁc human CD4+regulatory T cells and their ligands: doi: 10.2217/imt-2016-0119 implications for immunotherapy. Immunity. (2004) 20:107–18. 153. Frenel J-S, Le Tourneau C, O’Neil B, Ott PA, Piha-Paul SA, Gomez-Roca C, doi: 10.1016/S1074-7613(03)00359-5 et al. Safety and eﬃcacy of pembrolizumab in advanced, programmed death Frontiers in Immunology | www.frontiersin.org 18 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer ligand 1–positive cervical cancer: results from the phase Ib KEYNOTE-028 Immunol Today. (1993) 14:353–6. doi: 10.1016/0167-5699(93) trial. J Clin Oncol. (2017) 35:4035–41. doi: 10.1200/JCO.2017.74.5471 90235-D 154. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. 171. Mjösberg J, Berg G, Jenmalm MC, Ernerudh J. FOXP3+ regulatory Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. T cells and T Helper 1, T Helper 2, and T Helper 17 cells in (2015) 372:2521–32. doi: 10.1056/NEJMoa1503093 human early pregnancy Decidua1. Biol Reprod. (2010) 82:698–705. 155. Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, doi: 10.1095/biolreprod.109.081208 et al. Pembrolizumab versus ipilimumab for advanced melanoma: 172. Erkers T, Stikvoort A, Uhlin M. Lymphocytes in placental tissues: immune ﬁnal overall survival results of a multicentre, randomised, open- regulation and translational possibilities for immunotherapy. Stem Cells Int. label phase 3 study (KEYNOTE-006). Lancet. (2017) 390:1853–62. (2017) 2017:1–17. doi: 10.1155/2017/5738371 doi: 10.1016/S0140-6736(17)31601-X 173. Robertson SA, Care AS, Moldenhauer LM. Regulatory T cells in embryo 156. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, implantation and the immune response to pregnancy. J Clin Invest. (2018) et al. Combined nivolumab and ipilimumab or monotherapy in untreated 128:4224–35. doi: 10.1172/JCI122182 melanoma. N Engl J Med. (2015) 373:23–34. doi: 10.1056/NEJMoa1504030 174. Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T- 157. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. cell paradigm in pregnancy. Am J Reprod Immunol. (2010) 63:601–10. Nivolumab versus chemotherapy in patients with advanced melanoma who doi: 10.1111/j.1600-0897.2010.00852.x progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, 175. Chavan AR, Griﬃth OW, Wagner GP. The inﬂammation paradox in the controlled, open-label, phase 3 trial. Lancet Oncol. (2015) 16:375–84. evolution of mammalian pregnancy: turning a foe into a friend. Curr Opin doi: 10.1016/S1470-2045(15)70076-8 Genet Dev. (2017) 47:24–32. doi: 10.1016/j.gde.2017.08.004 158. Andersen MH. The speciﬁc targeting of immune regulation: T-cell responses 176. Powell RM. Novel T Cell Function and Speciﬁcity at the Human Maternal- against Indoleamine 2,3-dioxygenase. Cancer Immunol Immunother. (2012) Fetal Interface. (2018) Available online at: http://etheses.bham.ac.uk/8334/ 61:1289–97. doi: 10.1007/s00262-012-1234-4 (accessed September 4, 2018). 159. Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, et al. 177. Tilburgs T, Scherjon SA, van der Mast BJ, Haasnoot GW, Versteeg- Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers V.D.Voort-Maarschalk M, Roelen DL, et al. Fetal-maternal HLA-C of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res. mismatch is associated with decidual T cell activation and induction (2007) 67:792–801. doi: 10.1158/0008-5472.CAN-06-2925 of functional T regulatory cells. J Reprod Immunol. (2009) 82:147–56. 160. Munn DH. Indoleamine 2,3-dioxygenase, tumor-induced tolerance doi: 10.1016/j.jri.2009.05.003 and counter-regulation. Curr Opin Immunol. (2006) 18:220–5. 178. Tafuri A, Alferink J, Möller P, Hämmerling GJ, Arnold B. T cell awareness doi: 10.1016/j.coi.2006.01.002 of paternal alloantigens during pregnancy. Science. (1995) 270:630–3. 161. Mitchell TC, Hamid O, Smith DC, Bauer TM, Wasser JS, Olszanski doi: 10.1126/science.270.5236.630 AJ, et al. Epacadostat plus pembrolizumab in patients with advanced 179. Gleicher N, Kushnir VA, Barad DH. Redirecting reproductive immunology solid tumors: phase I results from a multicenter, open-label phase research toward pregnancy as a period of temporary immune tolerance. J I/II trial (ECHO-202/KEYNOTE-037). J Clin Oncol. (2018) 36:3223–30. Assist Reprod Genet. (2017) 34:425–30. doi: 10.1007/s10815-017-0874-x doi: 10.1200/JCO.2018.78.9602 180. Jiang SP, Vacchio MS. Multiple mechanisms of peripheral T cell tolerance to 162. Long GV, Dummer R, Hamid O, Gajewski T, Caglevic C, Dalle S, et al. the fetal “allograft”. J Immunol. (1998) 160:3086–90. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in 181. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat patients (pts) with unresectable or metastatic melanoma: results of the Rev Immunol. (2003) 3:223–32. doi: 10.1038/nri1029 phase 3 ECHO-301/KEYNOTE-252 study. J Clin Oncol. (2018) 36:108. 182. Shima T, Sasaki Y, Itoh M, Nakashima A, Ishii N, Sugamura K, et al. doi: 10.1200/JCO.2018.36.15_suppl.108 Regulatory T cells are necessary for implantation and maintenance of early 163. Iversen TZ, Engell-Noerregaard L, Ellebaek E, Andersen R, Larsen SK, pregnancy but not late pregnancy in allogeneic mice. J Reprod Immunol. Bjoern J, et al. Long-lasting disease stabilization in the absence of toxicity (2010) 85:121–9. doi: 10.1016/j.jri.2010.02.006 in metastatic lung cancer patients vaccinated with an epitope derived 183. Rusterholz C, Hahn S, Holzgreve W. Role of placentally produced from indoleamine 2,3 dioxygenase. Clin Cancer Res. (2014) 20:221–32. inﬂammatory and regulatory cytokines in pregnancy and the doi: 10.1158/1078-0432.CCR-13-1560 etiology of preeclampsia. Semin Immunopathol. (2007) 29:151–62. 164. Antony PA, Paulos CM, Ahmadzadeh M, Akpinarli A, Palmer DC, Sato doi: 10.1007/s00281-007-0071-6 N, et al. Interleukin-2-dependent mechanisms of tolerance and immunity 184. Apps R, Murphy SP, Fernando R, Gardner L, Ahad T, Moﬀett A. Human in vivo. J Immunol. (2006) 176:5255–66. doi: 10.4049/jimmunol.176.9.5255 leucocyte antigen (HLA) expression of primary trophoblast cells and 165. Maury S, Lemoine FM, Hicheri Y, Rosenzwajg M, Badoual C, Cherai placental cell lines, determined using single antigen beads to characterize M, et al. CD4+CD25+ regulatory T cell depletion improves the allotype speciﬁcities of anti-HLA antibodies. Immunology. (2009) 127:26–39. graft-versus-tumor eﬀect of donor lymphocytes after allogeneic doi: 10.1111/j.1365-2567.2008.03019.x hematopoietic stem cell transplantation. Sci Transl Med. (2010) 2:41ra52. 185. Solders M, Gorchs L, Erkers T, Lundell AC, Nava S, Gidlöf S, et al. doi: 10.1126/scitranslmed.3001302 MAIT cells accumulate in placental intervillous space and display a highly 166. Levings MK, Sangregorio R, Roncarolo M-G. Human CD25+CD4+ T cytotoxic phenotype upon bacterial stimulation. Sci Rep. (2017) 7:6123. regulatory cells suppress naive and memory T cell proliferation and can be doi: 10.1038/s41598-017-06430-6 expanded in vitro without loss of function. J Exp Med. (2001) 193:1295–302. 186. Moldenhauer LM, Diener KR, Thring DM, Brown MP, Hayball JD, doi: 10.1084/jem.193.11.1295 Robertson SA. Cross-presentation of male seminal ﬂuid antigens elicits T cell 167. Blat D, Zigmond E, Alteber Z, Waks T, Eshhar Z. Suppression of murine activation to initiate the female immune response to pregnancy. J Immunol. colitis and its associated cancer by carcinoembryonic antigen-speciﬁc (2009) 182:8080–93. doi: 10.4049/jimmunol.0804018 regulatory T cells. Mol Ther. (2014) 22:1018–28. doi: 10.1038/mt.2014.41 187. Jin LP, Chen QY, Zhang T, Guo PF, Li DJ. The CD4+CD25bright regulatory 168. Fransson M, Piras E, Burman J, Nilsson B, Essand M, Lu B, et al. T cells and CTLA-4 expression in peripheral and decidual lymphocytes are CAR/FoxP3-engineered T regulatory cells target the CNS and suppress down-regulated in human miscarriage. Clin Immunol. (2009) 133:402–10. EAE upon intranasal delivery. J Neuroinﬂammation. (2012) 9:576. doi: 10.1016/J.CLIM.2009.08.009 doi: 10.1186/1742-2094-9-112 188. Jasper MJ, Tremellen KP, Robertson SA. Primary unexplained infertility is 169. Raﬁq S, Yeku OO, Jackson HJ, Purdon TJ, van Leeuwen DG, Drakes associated with reduced expression of the T-regulatory cell transcription DJ, et al. Targeted delivery of a PD-1-blocking scFV by CAR-T cells factor Foxp3 in endometrial tissue. Mol Hum Reprod. (2006) 12:301–8. enhances anti-tumor eﬃcacy in vivo. Nat Biotechnol. (2018) 36:847–58. doi: 10.1093/molehr/gal032 doi: 10.1038/nbt.4195 189. Kallikourdis M, Betz AG. Periodic accumulation of regulatory T cells in the 170. Wegmann TG, Lin H, Mosmann TR. Bidirectional cytokine interactions in uterus: Preparation for the implantation of a semi-allogeneic fetus? PLoS the maternal-fetal relationshi : is successful pregnancy a Th 2 phenomenon? ONE. (2007) 2:e382. doi: 10.1371/journal.pone.0000382 Frontiers in Immunology | www.frontiersin.org 19 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer 190. Robertson SA, Guerin LR, Moldenhauer LM, Hayball JD. Activating fertilization and pregnancy outcome. Tissue Antigens. (2004) 64:66–9. T regulatory cells for tolerance in early pregnancy-the contribution of doi: 10.1111/j.1399-0039.2004.00239.x seminal ﬂuid. J Reprod Immunol. (2009) 83:109–16. doi: 10.1016/j.jri.2009. 209. Ishitani A, Sageshima N, Lee N, Dorofeeva N, Hatake K, Marquardt 08.003 H, et al. Protein expression and peptide binding suggest unique 191. Sasaki Y, Darmochwal-Kolarz D, Suzuki D, Sakai M, Ito M, Shima T, and interacting functional roles for HLA-E, F, and G in maternal- et al. Proportion of peripheral blood and decidual CD4(+) CD25(bright) placental immune recognition. J Immunol. (2003) 171:1376–84. regulatory T cells in pre-eclampsia. Clin Exp Immunol. (2007) 149:139–45. doi: 10.4049/jimmunol.171.3.1376 doi: 10.1111/j.1365-2249.2007.03397.x 210. Contini P, Ghio M, Poggi A, Filaci G, Indiveri F, Ferrone S, et al. Soluble 192. Santner-Nanan B, Peek MJ, Khanam R, Richarts L, Zhu E, Fazekas de St. HLA-A,-B,-C and -G molecules induce apoptosis in T and NK CD8+ cells Groth B, et al. Systemic increase in the ratio between Foxp3+ and IL-17- and inhibit cytotoxic T cell activity through CD8 ligation. Eur J Immunol. producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J (2003) 33:125–34. doi: 10.1002/immu.200390015 Immunol. (2009) 183:7023–30. doi: 10.1111/j.1096-3642.1945.tb00854.x 211. Horuzsko A, Lenfant F, Munn DH, Mellor AL. Maturation of antigen- 193. Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal presenting cells is compromised in HLA-G transgenic mice. Int Immunol. human pregnancy is associated with an elevation in the immune suppressive (2001) 13:385–94. doi: 10.1093/intimm/13.3.385 CD25 + CD4 + regulatory T-cell subset. Immunology. (2004) 112:38–43. 212. LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED. HLA- doi: 10.1111/j.1365-2567.2004.01869.x G1-expressing antigen-presenting cells induce immunosuppressive 194. Heikkinen J, Möttönen M, Alanen A, Lassila O. Phenotypic characterization CD4+ T cells. Proc Natl Acad Sci USA. (2004) 101:7064–9. of regulatory T cells in the human decidua. Clin Exp Immunol. (2004) doi: 10.1073/pnas.0401922101 136:373–8. doi: 10.1111/j.1365-2249.2004.02441.x 213. Tang X, Maricic I, Purohit N, Bakamjian B, Reed-Loisel LM, Beeston 195. Winger EE, Reed JL. Low Circulating CD4+ CD25+ Foxp3+ T T, et al. Regulation of immunity by a novel population of Qa-1- regulatory cell levels predict miscarriage risk in newly pregnant women restricted CD8 +TCR + T cells. J Immunol. (2006) 177:7645–55. with a history of failure. Am J Reprod Immunol. (2011) 66:320–8. doi: 10.4049/jimmunol.177.11.7645 doi: 10.1111/j.1600-0897.2011.00992.x 214. Zhou C, Wu J, Borillo J, Torres L, McMahon J, Lou YH. Potential roles 196. Kofod L, Lindhard A, Hviid TVF. Implications of uterine NK cells and of a special CD8 + cell population and CC chemokine thymus-expressed regulatory T cells in the endometrium of infertile women. Hum Immunol. chemokine in ovulation related inﬂammation. J Immunol. (2009) 182:596– (2018) 79:693–701. doi: 10.1016/j.humimm.2018.07.003 603. doi: 10.4049/jimmunol.182.1.596 197. Abdolmohammadi Vahid S, Ghaebi M, Ahmadi M, Nouri M, Danaei 215. Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman S, Aghebati-Maleki L, et al. Altered T-cell subpopulations in recurrent GJ, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during pregnancy loss patients with cellular immune abnormalities. J Cell Physiol. normal and autoimmune responses. Eur J Immunol. (2003) 33:2706–16. (2018) 234:4924–33. doi: 10.1002/jcp.27290 doi: 10.1002/eji.200324228 198. Chen T, Darrasse-Jeze G, Bergot AS, Courau T, Churlaud G, Valdivia K, et al. 216. Mor G, Gutierrez LS, Eliza M, Kahyaoglu F, Arici A. Fas-Fas Self-speciﬁc memory regulatory t cells protect embryos at implantation in ligand system-induced apoptosis in human placenta and gestational mice. J Immunol. (2013) 191:2273–81. doi: 10.4049/jimmunol.1202413 trophoblastic disease. Am J Reprod Immunol. (1998) 40:89–94. 199. Kieﬀer TEC, Faas MM, Scherjon SA, Prins JR. Pregnancy persistently doi: 10.1111/j.1600-0897.1998.tb00396.x aﬀects memory T cell populations. J Reprod Immunol. (2017) 119:1–8. 217. Stenqvist AC, Nagaeva O, Baranov V, Mincheva-Nilsson L. Exosomes doi: 10.1016/j.jri.2016.11.004 secreted by human placenta carry functional Fas Ligand and TRAIL 200. Liu S, Diao L, Huang C, Li Y, Zeng Y, Kwak-Kim JYH. The role of decidual molecules and convey apoptosis in activated immune cells, suggesting immune cells on human pregnancy. J Reprod Immunol. (2017) 124:44–53. exosome-mediated immune privilege of the fetus. J Immunol. (2013) doi: 10.1016/j.jri.2017.10.045 191:5515–23. doi: 10.4049/jimmunol.1301885 201. Munoz-Suano A, Hamilton AB, Betz AG. Gimme shelter: the 218. Vacchio MS, Hodes RJ. Fetal expression of Fas Ligand is necessary immune system during pregnancy. Immunol Rev. (2011) 241:20–38. and suﬃcient for induction of CD8 T cell tolerance to the fetal doi: 10.1111/j.1600-065X.2011.01002.x antigen H-Y during pregnancy. J Immunol. (2005) 174:4657–61. 202. Muzzio D, Zenclussen AC, Jensen F. The role of B cells in pregnancy: doi: 10.4049/jimmunol.174.8.4657 the good and the bad. Am J Reprod Immunol. (2013) 69:408–12. 219. Hönig A, Rieger L, Kapp M, Sütterlin M, Dietl J, Kämmerer U. Indoleamine doi: 10.1111/aji.12079 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast 203. Ramhorst R, Grasso E, Paparini D, Hauk V, Gallino L, Calo G, et al. Decoding supports role of the enzyme for materno-fetal tolerance. J Reprod Immunol. the chemokine network that links leukocytes with decidual cells and the (2004) 61:79–86. doi: 10.1016/J.JRI.2003.11.002 trophoblast during early implantation. Cell Adh Migr. (2016) 10:197–207. 220. Zong S, Li C, Luo C, Zhao X, Liu C, Wang K, et al. Dysregulated expression doi: 10.1080/19336918.2015.1135285 of IDO may cause unexplained recurrent spontaneous abortion through 204. Chiossone L, Vacca P, Orecchia P, Croxatto D, Damonte P, Astigiano suppression of trophoblast cell proliferation and migration. Sci Rep. (2016) S, et al. In vivo generation of decidual natural killer cells from 6:19916. doi: 10.1038/srep19916 resident hematopoietic progenitors. Haematologica. (2014) 99:448–57. 221. Ramhorst R, Fraccaroli L, Aldo P, Alvero AB, Cardenas I, Leirós CP, doi: 10.3324/haematol.2013.091421 et al. Modulation and recruitment of inducible regulatory T cells by 205. Vacca P, Vitale C, Montaldo E, Conte R, Cantoni C, Fulcheri E, et al. ﬁrst trimester trophoblast cells. Am J Reprod Immunol. (2012) 67:17–27. CD34 + hematopoietic precursors are present in human decidua and doi: 10.1111/j.1600-0897.2011.01056.x diﬀerentiate into natural killer cells upon interaction with stromal cells. 222. Roth I, Corry DB, Locksley RM, Abrams JS, Litton MJ, Fisher SJ. Human Proc Natl Acad Sci USA. (2010) 108:2402–7. doi: 10.1073/pnas.10162 placental cytotrophoblasts produce the immunosuppressive cytokine 57108 interleukin 10. J Exp Med. (1996) 184:539–48. doi: 10.1084/jem.184.2.539 206. Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia 223. Moreau P, Adrian-Cabestre F, Menier C, Guiard V, Gourand L, Dausset J, F, et al. Unique chemotactic response proﬁle and speciﬁc expression of et al. IL-10 selectively induces HLA-G expression in human trophoblasts and chemokine receptors Ccr4 and Ccr8 by Cd4 + Cd25 + regulatory T cells. monocytes. Int Immunol. (1999) 11:803–11. J Exp Med. (2001) 194:847–54. doi: 10.1084/jem.194.6.847 224. Habicht A, Dada S, Jurewicz M, Fife BT, Yagita H, Azuma M, et al. A link 207. Barsheshet Y, Wildbaum G, Levy E, Vitenshtein A, Akinseye C, Griggs J, between PDL1 and T regulatory cells in fetomaternal tolerance. J Immunol. et al. CCR8 + FOXp3 + T reg cells as master drivers of immune regulation. (2007) 179:5211–19. doi: 10.4049/jimmunol.179.8.5211 Proc Natl Acad Sci USA. (2017) 114:6086–91. doi: 10.1073/pnas.16212 225. Grozdics E, Berta L, Bajnok A, Veres G, Ilisz I, Klivényi P Jr, et al. B7 80114 costimulation and intracellular indoleamine-2, 3-dioxygenase (IDO) 208. Hviid TVF, Hylenius S, Lindhard A, Christiansen OB. Association expression in peripheral blood B7 costimulation and intracellular between human leukocyte antigen-G genotype and success of in vitro indoleamine-2, 3-dioxygenase (IDO) expression in peripheral Frontiers in Immunology | www.frontiersin.org 20 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer blood of healthy pregnant and non-pregnant women 3-dioxygen. 238. Fukui A, Yokota M, Funamizu A, Nakamua R, Fukuhara R, Yamada K, BMC Pregnancy Childbirth. (2014) 14:1–9. doi: 10.1186/1471-239 et al. Changes of NK cells in preeclampsia. Am J Reprod Immunol. (2012) 3-14-306 67:278–86. doi: 10.1111/j.1600-0897.2012.01120.x 226. Zhang Y, Liu Z, Tian M, Hu X, Wang L, Ji J, et al. The altered PD- 239. Katano K, Suzuki S, Ozaki Y, Suzumori N, Kitaori T, Sugiura-Ogasawara 1/PD-L1 pathway delivers the ‘one-two punch’ eﬀects to promote the M. Peripheral natural killer cell activity as a predictor of recurrent Treg/Th17 imbalance in pre-eclampsia. Cell Mol Immunol. (2018) 15:710– pregnancy loss: a large cohort study. Fertil Steril. (2013) 100:1629–34. 23. doi: 10.1038/cmi.2017.70 doi: 10.1016/j.fertnstert.2013.07.1996 227. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, 240. Terme M, Chaput N, Combadiere B, Ma A, Ohteki T, Zitvogel L. Regulatory Kuchroo VK, et al. PD-L1 regulates the development, maintenance, and T cells control dendritic cell/NK cell cross-talk in lymph nodes at the function of induced regulatory T cells. J Exp Med. (2009) 206:3015–29. steady state by inhibiting CD4+ self-reactive T cells. J Immunol. (2008) doi: 10.1084/jem.20090847 180:4679–86. doi: 10.4049/jimmunol.180.7.4679 228. D’Addio F, Riella LV, Mfarrej BG, Chabtini L, Adams LT, Yeung M, et al. 241. Ghiringhelli F, Ménard C, Terme M, Flament C, Taieb J, Chaput N, et al. The link between the PDL1 costimulatory pathway and Th17 in fetomaternal CD4 CD25 regulatory T cells inhibit natural killer cell functions in a tolerance. J Immunol. (2011) 187:4530–41. doi: 10.4049/jimmunol.1002031 transforming growth factor-dependent manner. J Exp Med. (2005) 202:1075– 229. Wakkach A, Fournier N, Brun V, Breittmayer JP, Cottrez F, Groux 1085. doi: 10.1084/jem.20051511 H. Characterization of dendritic cells that induce tolerance and T 242. Keskin DB, Allan DSJ, Rybalov B, Andzelm MM, Stern JNH, Kopcow HD, regulatory 1 cell diﬀerentiation in vivo. Immunity. (2003) 18:605–17. et al. TGFbeta promotes conversion of CD16+ peripheral blood NK cells doi: 10.1016/S1074-7613(03)00113-4 into CD16- NK cells with similarities to decidual NK cells. Proc Natl Acad 230. Miyazaki S, Tsuda H, Sakai M, Hori S, Sasaki Y, Futatani T, et al. Sci USA. (2007) 104:3378–83. doi: 10.1073/pnas.0611098104 Predominance of Th2-promoting dendritic cells in early human pregnancy 243. Fu B, Li X, Sun R, Tong X, Ling B, Tian Z, et al. Natural killer cells decidua. J Leukoc Biol. (2003) 74:514–22. doi: 10.1189/jlb.1102566 promote immune tolerance by regulating inﬂammatory TH17 cells at the 231. Blois SM, Alba Soto CD, Tometten M, Klapp BF, Margni RA, Arck human maternal-fetal interface. Proc Natl Acad Sci USA. (2013) 110:E231– PC. Lineage, maturity, and phenotype of uterine murine dendritic cells 40. doi: 10.1073/pnas.1206322110 throughout gestation indicate a protective role in maintaining pregnancy. 244. Renaud SJ, Cotechini T, Quirt JS, Macdonald-Goodfellow SK, Othman M, Biol Reprod. (2004) 70:1018–23. doi: 10.1095/biolreprod.103.022640 Graham CH. Spontaneous pregnancy loss mediated by abnormal maternal 232. Tiemessen MM, van Herwijnen MJC, Evans HG, Jagger AL, Taams LS, John inﬂammation in rats is linked to deﬁcient uteroplacental perfusion. J S. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of Immunol. (2011) 186:1799–808. doi: 10.4049/jimmunol.1002679 human monocytes/macrophages. Proc Natl Acad Sci USA. (2007) 104:19446– 245. Heitmann RJ, Weitzel RP, Feng Y, Segars JH, Tisdale JF, Wolﬀ EF. Maternal 51. doi: 10.1073/pnas.0706832104 T regulatory cell depletion impairs embryo implantation which can be 233. Schumacher A, Wafula PO, Teles A, El-Mousleh T, Linzke N, corrected with adoptive T regulatory cell transfer. Reprod Sci. (2017) Zenclussen ML, et al. Blockage of heme oxygenase-1 abrogates the 24:1014–24. doi: 10.1177/1933719116675054 protective eﬀect of regulatory T cells on murine pregnancy and 246. Wilczynski JR, Kalinka J, Radwan M. The role of T-regulatory cells promotes the maturation of dendritic cells. PLoS ONE. (2012) 7:e42301. in pregnancy and cancer. Front Biosci. (2008) 13:2275–89. doi: 10.274 doi: 10.1371/journal.pone.0042301 1/2841 234. Mellor AL, Sivakumar J, Chandler P, Smith K, Molina H, Mao D, et al. Prevention of T cell-driven complement activation and inﬂammation by Conﬂict of Interest Statement: The authors declare that the research was tryptophan catabolism during pregnancy. Nat Immunol. (2001) 2:64–8. conducted in the absence of any commercial or ﬁnancial relationships that could doi: 10.1038/83183 be construed as a potential conﬂict of interest. 235. Vacca P, Cantoni C, Vitale M, Prato C, Canegallo F, Fenoglio D, et al. Crosstalk between decidual NK and CD14+ myelomonocytic cells results in Copyright © 2019 Jørgensen, Persson and Hviid. This is an open-access article induction of Tregs and immunosuppression. Proc Natl Acad Sci USA. (2010) distributed under the terms of the Creative Commons Attribution License (CC BY). 107:11918–23. doi: 10.1073/pnas.1001749107 The use, distribution or reproduction in other forums is permitted, provided the 236. Moﬀett A, Colucci F. Uterine NK cells: active regulators at the maternal-fetal original author(s) and the copyright owner(s) are credited and that the original interface. J Clin Invest. (2014) 124:1872–79. doi: 10.1172/JCI68107 publication in this journal is cited, in accordance with accepted academic practice. 237. Moﬀett-King A. Natural killer cells and pregnancy. Nat Rev Immunol. (2002) No use, distribution or reproduction is permitted which does not comply with these 2:656–63. doi: 10.1038/nri886 terms. Frontiers in Immunology | www.frontiersin.org 21 May 2019 | Volume 10 | Article 911 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Frontiers in Immunology Unpaywall http://www.deepdyve.com/lp/unpaywall/the-tolerogenic-function-of-regulatory-t-cells-in-pregnancy-and-cancer-RHdqfD37nl

Loading next page...

References (256)

Wenna Melsted, S. Matzen, M. Andersen, T. Hviid (2017)
The choriocarcinoma cell line JEG-3 upregulates regulatory T cell phenotypes and modulates pro-inflammatory cytokines through HLA-G.
Cellular immunology, 324
M. Herrath, L. Harrison (2003)
Regulatory lymphocytes: Antigen-induced regulatory T cells in autoimmunity
Nature Reviews Immunology, 3
Belal Chaudhary, E. Elkord (2016)
Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting
Vaccines, 4
R. Bacchetta, C. Sartirana, M. Levings, C. Bordignon, S. Narula, M. Roncarolo (2002)
Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines
European Journal of Immunology, 32
R. Khattri, T. Cox, Sue-Ann Yasayko, F. Ramsdell (2003)
An essential role for Scurfin in CD4+CD25+ T regulatory cells
Nature Immunology, 4
T. Whiteside (2015)
The role of regulatory T cells in cancer immunology
Immunotargets and Therapy, 4
D. Frey, R. Droeser, C. Viehl, I. Zlobec, A. Lugli, U. Zingg, D. Oertli, C. Kettelhack, L. Terracciano, L. Tornillo (2010)
High frequency of tumor‐infiltrating FOXP3+ regulatory T cells predicts improved survival in mismatch repair‐proficient colorectal cancer patients
International Journal of Cancer, 126
P. Savage, Daniel Leventhal, Sven Malchow (2014)
Shaping the repertoire of tumor‐infiltrating effector and regulatory T cells
Immunological Reviews, 259
T. Tilburgs, S. Scherjon, B. Mast, G. Haasnoot, Minke Voort-Maarschalk, D. Roelen, J. Rood, F. Claas (2009)
Fetal-maternal HLA-C mismatch is associated with decidual T cell activation and induction of functional T regulatory cells.
Journal of reproductive immunology, 82 2
F. Ichihara, K. Kono, Akihiro Takahashi, Hiromichi Kawaida, H. Sugai, H. Fujii (2003)
Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers.
Clinical cancer research : an official journal of the American Association for Cancer Research, 9 12
R. Ramhorst, E. Grasso, Daniel Paparini, V. Hauk, L. Gallino, G. Calo, Daiana Vota, C. Leirós (2016)
Decoding the chemokine network that links leukocytes with decidual cells and the trophoblast during early implantation
Cell Adhesion & Migration, 10
U. Feger, E. Tolosa, Yu‐Hwa Huang, A. Waschbisch, T. Biedermann, A. Melms, H. Wiendl (2007)
HLA-G expression defines a novel regulatory T-cell subset present in human peripheral blood and sites of inflammation.
Blood, 110 2
J. LeMaoult, I. Krawice-Radanne, J. Dausset, E. Carosella (2004)
HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4+ T cells.
Proceedings of the National Academy of Sciences of the United States of America, 101 18
M. Plattén, W. Wick, B. Eynde (2012)
Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion.
Cancer research, 72 21
Wanjun Chen, W. Jin, N. Hardegen, K. Lei, Li Li, N. Marinos, G. McGrady, S. Wahl (2003)
Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3
The Journal of Experimental Medicine, 198
Li-Yuan Chang, Yung-Chang Lin, J. Mahalingam, Ching-Tai Huang, Ten-Wen Chen, Chiao-Wen Kang, Hui-min Peng, Yu‐Yi Chu, J. Chiang, A. Dutta, Y. Day, Tse-Ching Chen, C. Yeh, Chun-Yen Lin (2012)
Tumor-Derived Chemokine CCL5 Enhances TGF- b – Mediated Killing of CD8 þ T Cells in Colon Cancer by T-Regulatory Cells
J. Mjösberg, G. Berg, M. Jenmalm, J. Ernerudh (2010)
FOXP3+ Regulatory T Cells and T Helper 1, T Helper 2, and T Helper 17 Cells in Human Early Pregnancy Decidua1
, 82
H. Jonuleit, E. Schmitt (2003)
The Regulatory T Cell Family: Distinct Subsets and their Interrelations 2
The Journal of Immunology, 171
M. Vacchio, R. Hodes (2005)
Fetal Expression of Fas Ligand Is Necessary and Sufficient for Induction of CD8 T Cell Tolerance to the Fetal Antigen H-Y during Pregnancy
The Journal of Immunology, 174
T. Mitchell, O. Hamid, David Smith, T. Bauer, J. Wasser, A. Olszanski, J. Luke, A. Balmanoukian, E. Schmidt, Yufan Zhao, Xiaohua Gong, J. Maleski, L. Leopold, T. Gajewski (2018)
Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)
Journal of Clinical Oncology, 36
Corinne Tanchot, M. Terme, M. Terme, H. Péré, H. Péré, T. Tran, T. Tran, N. Benhamouda, N. Benhamouda, M. Strioga, C. Banissi, C. Banissi, L. Galluzzi, G. Kroemer, E. Tartour, E. Tartour (2013)
Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance
Cancer Microenvironment, 6
N. Gleicher, V. Kushnir, D. Barad (2017)
Redirecting reproductive immunology research toward pregnancy as a period of temporary immune tolerance
Journal of Assisted Reproduction and Genetics, 34
Z Liu, M Li, Z Jiang, X Wang (2018)
A comprehensive immunologic portrait of triple-negative breast cancer
Transl Oncol, 11
A. Iellem, M. Mariani, R. Lang, H. Recalde, P. Panina-Bordignon, F. Sinigaglia, D. d'Ambrosio (2001)
Unique Chemotactic Response Profile and Specific Expression of Chemokine Receptors Ccr4 and Ccr8 by Cd4+Cd25+ Regulatory T Cells
The Journal of Experimental Medicine, 194
C. Baecher-Allan, Julia Brown, G. Freeman, D. Hafler (2001)
CD4+CD25high Regulatory Cells in Human Peripheral Blood1
The Journal of Immunology, 167
M. Levings, R. Sangregorio, M. Roncarolo (2001)
Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function
The Journal of Experimental Medicine, 193
Sabine Schreck, D. Friebel, M. Buettner, L. Distel, G. Grabenbauer, L. Young, G. Niedobitek (2009)
Prognostic impact of tumour‐infiltrating Th2 and regulatory T cells in classical Hodgkin lymphoma
Hematological Oncology, 27
M. Beyer, M. Kochanek, Kamruz Darabi, A. Popov, M. Jensen, E. Endl, P. Knolle, Roman Thomas, M. Bergwelt-Baildon, S. Debey, M. Hallek, J. Schultze (2005)
Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine.
Blood, 106 6
Yong‐Hong Zhang, Zhaozhao Liu, Mei Tian, Xiaohui Hu, Liling Wang, Jinlu Ji, A. Liao (2017)
The altered PD-1/PD-L1 pathway delivers the ‘one-two punch’ effects to promote the Treg/Th17 imbalance in pre-eclampsia
Cellular & Molecular Immunology, 15
Wenna Melsted, Lasse Johansen, J. Lock‐Andersen, N. Behrendt, J. Eriksen, M. Bzorek, T. Scheike, T. Hviid (2017)
HLA class Ia and Ib molecules and FOXP3+ TILs in relation to the prognosis of malignant melanoma patients.
Clinical immunology, 183
Sven Malchow, Daniel Leventhal, Saki Nishi, Benjamin Fischer, Lynn Shen, G. Paner, A. Amit, Chulho Kang, Jenna Geddes, J. Allison, N. Socci, P. Savage (2013)
Aire-Dependent Thymic Development of Tumor-Associated Regulatory T Cells
Science, 339
Takeshi Takahashi, Y. Kuniyasu, M. Toda, N. Sakaguchi, M. Itoh, M. Iwata, J. Shimizu, S. Sakaguchi (1998)
Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state.
International immunology, 10 12
J. Wilczyński, J. Kalinka, M. Radwan (2008)
The role of T-regulatory cells in pregnancy and cancer.
Frontiers in bioscience : a journal and virtual library, 13
G. Stephens, R. McHugh, M. Whitters, D. Young, D. Luxenberg, B. Carreno, M. Collins, E. Shevach (2004)
Engagement of Glucocorticoid-Induced TNFR Family-Related Receptor on Effector T Cells by its Ligand Mediates Resistance to Suppression by CD4+CD25+ T Cells
The Journal of Immunology, 173
Helen Wang, Dean Lee, Guangyong Peng, Zhong Guo, Yanchun Li, Y. Kiniwa, E. Shevach, Rong-Fu Wang (2004)
Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy.
Immunity, 20 1
R. Bhatnagar, J. Zabriskie, A. Rausen (1975)
Cellular immune responses to methylcholanthrene-induced fibrosarcoma in BALB/c mice
The Journal of Experimental Medicine, 142
A. Mellor, J. Sivakumar, P. Chandler, Kimberly Smith, H. Molina, D. Mao, D. Munn (2001)
Prevention of T cell–driven complement activation and inflammation by tryptophan catabolism during pregnancy
Nature Immunology, 2
G. Mor, L. Gutierrez, M. Eliza, Ferahnaz Kahyaoglu, A. Arıcı (1998)
Fas‐Fas Ligand System‐Induced Apoptosis in Human Placenta and Gestational Trophoblastic Disease
American Journal of Reproductive Immunology, 40
J. Schachter, A. Ribas, G. Long, A. Arance, J. Grob, L. Mortier, A. Daud, M. Carlino, C. McNeil, M. Lotem, J. Larkin, P. Lorigan, B. Neyns, C. Blank, T. Petrella, O. Hamid, Honghong Zhou, S. Ebbinghaus, N. Ibrahim, C. Robert (2017)
Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)
The Lancet, 390
Loise Francisco, Victor Salinas, Keturah Brown, V. Vanguri, G. Freeman, V. Kuchroo, A. Sharpe (2009)
PD-L1 regulates the development, maintenance, and function of induced regulatory T cells
The Journal of Experimental Medicine, 206
Lars Ormandy, Tina Hillemann, H. Wedemeyer, M. Manns, T. Greten, F. Korangy (2005)
Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma.
Cancer research, 65 6
P. Vacca, C. Cantoni, M. Vitale, Carola Prato, F. Canegallo, D. Fenoglio, N. Ragni, L. Moretta, M. Mingari (2010)
Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression
Proceedings of the National Academy of Sciences, 107
C. Rusterholz, S. Hahn, W. Holzgreve (2007)
Role of placentally produced inflammatory and regulatory cytokines in pregnancy and the etiology of preeclampsia
Seminars in Immunopathology, 29
R. Motzer, N. Tannir, D. McDermott, O. Frontera, B. Melichar, T. Choueiri, E. Plimack, P. Barthélémy, C. Porta, S. George, T. Powles, F. Donskov, V. Neiman, C. Kollmannsberger, P. Salman, H. Gurney, R. Hawkins, A. Ravaud, M. Grimm, S. Bracarda, C. Barrios, Y. Tomita, D. Castellano, B. Rini, Allen Chen, S. Mekan, B. McHenry, M. Wind-Rotolo, J. Doan, Padmanee Sharma, H. Hammers, B. Escudier (2018)
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal‐Cell Carcinoma
The New England Journal of Medicine, 378
C. Ueshima, T. Kataoka, M. Hirata, A. Furuhata, E. Suzuki, M. Toi, T. Tsuruyama, Y. Okayama, H. Haga (2015)
The Killer Cell Ig-like Receptor 2DL4 Expression in Human Mast Cells and Its Potential Role in Breast Cancer Invasion
Cancer Immunology Research, 3
K. Kono, Hiromichi Kawaida, Akihiro Takahashi, H. Sugai, Kosaku Mimura, Naoto Miyagawa, H. Omata, H. Fujii (2006)
CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers
Cancer Immunology, Immunotherapy, 55
H. Waldmann, L. Graça, S. Cobbold, E. Adams, M. Tone, Y. Tone (2004)
Regulatory T cells and organ transplantation.
Seminars in immunology, 16 2
A. Bonertz, J. Weitz, D. Pietsch, N. Rahbari, C. Schlude, Y. Ge, S. Juenger, I. Vlodavsky, K. Khazaie, D. Jaeger, C. Reissfelder, D. Antolovic, M. Aigner, M. Koch, P. Beckhove (2009)
Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma.
The Journal of clinical investigation, 119 11
Shenyou Sun, X. Fei, Y. Mao, Xiumin Wang, D. Garfield, O. Huang, Jinglong Wang, Fei Yuan, Long Sun, Qi-xiang Yu, Xiaolong Jin, Jianhua Wang, K. Shen (2014)
PD-1+ immune cell infiltration inversely correlates with survival of operable breast cancer patients
Cancer Immunology, Immunotherapy, 63
E. Carosella, N. Rouas-Freiss, D. Roux, P. Moreau, J. LeMaoult (2015)
HLA-G: An Immune Checkpoint Molecule.
Advances in immunology, 127
Samaneh Vahid, Mahnaz Ghaebi, M. Ahmadi, M. Nouri, Shahla Danaei, L. Aghebati-Maleki, Reza Ardehaie, B. Yousefi, Parvin Hakimi, M. Hojjat-Farsangi, R. Rikhtegar, M. Yousefi (2018)
Altered T‐cell subpopulations in recurrent pregnancy loss patients with cellular immune abnormalities
Journal of Cellular Physiology, 234
Arun Chavan, O. Griffith, G. Wagner (2017)
The inflammation paradox in the evolution of mammalian pregnancy: turning a foe into a friend.
Current opinion in genetics & development, 47
L. Krausz, E. Fischer-Fodor, Z. Major, B. Fetica (2012)
Gitr-Expressing Regulatory T-Cell Subsets are Increased in Tumor-Positive Lymph Nodes from Advanced Breast Cancer Patients as Compared to Tumor-Negative Lymph Nodes
International Journal of Immunopathology and Pharmacology, 25
S. Blois, C. Soto, M. Tometten, B. Klapp, R. Margni, P. Arck (2004)
Lineage, Maturity, and Phenotype of Uterine Murine Dendritic Cells Throughout Gestation Indicate a Protective Role in Maintaining Pregnancy1
, 70
D. Munn (2006)
Indoleamine 2,3-dioxygenase, tumor-induced tolerance and counter-regulation.
Current opinion in immunology, 18 2
Zhixian Liu, Mengyuan Li, Zehang Jiang, Xiaosheng Wang (2017)
A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer
Translational Oncology, 11
Y. Sasaki, D. Darmochwal-Kolarz, D. Suzuki, M. Sakai, M. Ito, T. Shima, A. Shiozaki, J. Roliński, S. Saito (2007)
Proportion of peripheral blood and decidual CD4+ CD25bright regulatory T cells in pre‐eclampsia
Clinical & Experimental Immunology, 149
H. Gremmels, Olivier Jong, Diënty Hazenbrink, J. Fledderus, M. Verhaar (2017)
The Transcription Factor Nrf2 Protects Angiogenic Capacity of Endothelial Colony-Forming Cells in High-Oxygen Radical Stress Conditions
Stem Cells International, 2017
B. Santner‐Nanan, M. Peek, Roma Khanam, Luise Richarts, Erhua Zhu, B. Groth, R. Nanan (2009)
Systemic Increase in the Ratio between Foxp3+ and IL-17-Producing CD4+ T Cells in Healthy Pregnancy but Not in Preeclampsia1
The Journal of Immunology, 183
A. Tzankov, Cecile Meier, Petra Hirschmann, P. Went, S. Pileri, S. Dirnhofer (2008)
Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma
Haematologica, 93
L. Vence, A. Palucka, J. Fay, Tomoki Ito, Yong‐jun Liu, J. Banchereau, H. Ueno (2007)
Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma
Proceedings of the National Academy of Sciences, 104
K. Tarbell, S. Yamazaki, Kara Olson, Priscilla Toy, R. Steinman (2004)
T Cells , Expanded with Dendritic Cells Presenting a Single Autoantigenic Peptide , Suppress Autoimmune Diabetes
M. Andersen (2015)
Immune Regulation by Self-Recognition: Novel Possibilities for Anticancer Immunotherapy.
Journal of the National Cancer Institute, 107 9
T. Wegmann, Hui Lin, L. Guilbert, T. Mosmann (1993)
Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?
Immunology today, 14 7
G. Landskron, M. Fuente, P. Thuwajit, C. Thuwajit, M. Hermoso (2014)
Chronic Inflammation and Cytokines in the Tumor Microenvironment
Journal of Immunology Research, 2014
Lawrence Andrews, A. Marciscano, C. Drake, D. Vignali (2017)
LAG3 (CD223) as a cancer immunotherapy target
Immunological Reviews, 276
Philippe Moreau, F. Adrian-Cabestre, C. Menier, Virginie Guiard, L. Gourand, J. Dausset, E. Carosella, P. Paul (1999)
IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes.
International immunology, 11 5
S. Rafiq, O. Yeku, H. Jackson, Terence Purdon, Dayenne Leeuwen, Dylan Drakes, Mei Song, Matthew Miele, Zhuoning Li, Pei Wang, Su Yan, Jingyi Xiang, Xiaojing Ma, V. Seshan, R. Hendrickson, Cheng Liu, R. Brentjens (2018)
Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo
Nature biotechnology, 36
S. Wahl, N. Vázquez, Wanjun Chen (2004)
Regulatory T cells and transcription factors: gatekeepers in allergic inflammation.
Current opinion in immunology, 16 6
Shuzhen Liu, W. Foulkes, S. Leung, D. Gao, Sherman Lau, Z. Kos, T. Nielsen (2014)
Prognostic significance of FOXP3+ tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration
Breast Cancer Research : BCR, 16
A Bonertz, J Weitz, DK Pietsch, NN Rahbari, C Schlude, Y Ge (2009)
Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma
J Clin Investig, 119
Q. Tang, J. Adams, A. Tooley, Mingying Bi, B. Fife, P. Serra, P. Santamaria, R. Locksley, M. Krummel, J. Bluestone (2006)
Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice
Nature Immunology, 7
C. Miracco, V. Mourmouras, M. Biagioli, P. Rubegni, S. Mannucci, I. Monciatti, E. Cosci, P. Tosi, P. Luzi (2007)
Utility of tumour-infiltrating CD25+FOXP3+ regulatory T cell evaluation in predicting local recurrence in vertical growth phase cutaneous melanoma.
Oncology reports, 18 5
A. Thornton, P. Korty, D. Tran, E. Wohlfert, Patrick Murray, Y. Belkaid, E. Shevach (2010)
Expression of Helios, an Ikaros Transcription Factor Family Member, Differentiates Thymic-Derived from Peripherally Induced Foxp3+ T Regulatory Cells
The Journal of Immunology, 184
F. Hodi, M. Mihm, R. Soiffer, F. Haluska, M. Butler, M. Seiden, T. Davis, Rochele Henry-Spires, Suzanne Macrae, Ann Willman, R. Padera, M. Jaklitsch, S. Shankar, Teresa Chen, A. Korman, J. Allison, G. Dranoff (2003)
Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients
Proceedings of the National Academy of Sciences of the United States of America, 100
J. Frenel, C. Tourneau, B. O'Neil, P. Ott, S. Piha-Paul, C. Gomez-Roca, E. Brummelen, H. Rugo, S. Thomas, S. Saraf, Reshma Rangwala, A. Varga (2017)
Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1-Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 35 36
S. Robertson, Alison Care, L. Moldenhauer (2018)
Regulatory T cells in embryo implantation and the immune response to pregnancy
Journal of Clinical Investigation, 128
Yiftah Barsheshet, G. Wildbaum, Eran Levy, A. Vitenshtein, Chika Akinseye, J. Griggs, S. Lira, N. Karin (2017)
CCR8+FOXp3+ Treg cells as master drivers of immune regulation
Proceedings of the National Academy of Sciences, 114
A. Moffett, F. Colucci (2014)
Uterine NK cells: active regulators at the maternal-fetal interface.
The Journal of clinical investigation, 124 5
D. Muzzio, A. Zenclussen, F. Jensen (2013)
The Role of B Cells in Pregnancy: the Good and the Bad
American Journal of Reproductive Immunology, 69
Cindy Zhou, Jean Wu, Jason Borillo, Lisa Torres, J. McMahon, Y. Lou (2009)
Potential Roles of a Special CD8αα+ Cell Population and CC Chemokine Thymus-Expressed Chemokine in Ovulation Related Inflammation1
The Journal of Immunology, 182
Shi-Ping Jiang, M. Vacchio (1998)
Multiple mechanisms of peripheral T cell tolerance to the fetal "allograft".
Journal of immunology, 160 7
G. Darrasse-Jéze, A. Bergot, A. Durgeau, Fabienne Billiard, B. Salomon, J. Cohen, B. Bellier, K. Podsypanina, D. Klatzmann (2009)
Tumor emergence is sensed by self-specific CD44hi memory Tregs that create a dominant tolerogenic environment for tumors in mice.
The Journal of clinical investigation, 119 9
Alba Muñoz‐Suano, A. Hamilton, A. Betz (2011)
Gimme shelter: the immune system during pregnancy
Immunological Reviews, 241
R. Powell (2018)
Novel T cell function and specificity at the human maternal-fetal interface
I. Roth, D. Corry, R. Locksley, John Abrams, M. Litton, Susan Fisher (1996)
Human placental cytotrophoblasts produce the immunosuppressive cytokine interleukin 10
The Journal of Experimental Medicine, 184
Susann Pankratz, T. Ruck, S. Meuth, H. Wiendl (2016)
CD4(+)HLA-G(+) regulatory T cells: Molecular signature and pathophysiological relevance.
Human immunology, 77 9
S. Maury, F. Lemoine, Y. Hicheri, M. Rosenzwajg, C. Badoual, M. Cheraï, J. Beaumont, N. Azar, N. Dhédin, A. Sirvent, A. Buzyn, M. Rubio, S. Vigouroux, O. Montagne, D. Bories, F. Roudot-thoraval, J. Vernant, C. Cordonnier, D. Klatzmann, J. Cohen (2010)
CD4+CD25+ Regulatory T Cell Depletion Improves the Graft-Versus-Tumor Effect of Donor Lymphocytes After Allogeneic Hematopoietic Stem Cell Transplantation
Science Translational Medicine, 2
P. Vacca, C. Vitale, E. Montaldo, R. Conte, C. Cantoni, E. Fulcheri, Valeria Darretta, L. Moretta, M. Mingari (2011)
CD34+ hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells
Proceedings of the National Academy of Sciences, 108
A. Stenqvist, O. Nagaeva, V. Baranov, L. Mincheva-Nilsson (2013)
Exosomes Secreted by Human Placenta Carry Functional Fas Ligand and TRAIL Molecules and Convey Apoptosis in Activated Immune Cells, Suggesting Exosome-Mediated Immune Privilege of the Fetus
The Journal of Immunology, 191
A. Suto, H. Nakajima, K. Ikeda, S. Kubo, T. Nakayama, M. Taniguchi, Y. Saito, I. Iwamoto (2002)
CD4(+)CD25(+) T-cell development is regulated by at least 2 distinct mechanisms.
Blood, 99 2
S. Renaud, T. Cotechini, J. Quirt, S. Macdonald-Goodfellow, M. Othman, C. Graham (2011)
Spontaneous Pregnancy Loss Mediated by Abnormal Maternal Inflammation in Rats Is Linked to Deficient Uteroplacental Perfusion
The Journal of Immunology, 186
D. Blat, E. Zigmond, Zoya Alteber, T. Waks, Z. Eshhar (2014)
Suppression of murine colitis and its associated cancer by carcinoembryonic antigen-specific regulatory T cells.
Molecular therapy : the journal of the American Society of Gene Therapy, 22 5
M. Tiemessen, A. Jagger, H. Evans, Martijn Herwijnen, S. John, L. Taams (2007)
CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages
Proceedings of the National Academy of Sciences, 104
M. Levings, R. Sangregorio, F. Galbiati, S. Squadrone, R. Malefyt, M. Roncarolo (2001)
IFN-α and IL-10 Induce the Differentiation of Human Type 1 T Regulatory Cells1
The Journal of Immunology, 166
Weihong Liu, A. Putnam, Xu-yu Zhou, G. Szot, Michael Lee, Shirley Zhu, P. Gottlieb, P. Kapranov, T. Gingeras, Barbara Groth, C. Clayberger, David Soper, S. Ziegler, J. Bluestone (2006)
CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells
The Journal of Experimental Medicine, 203
T. Álvaro, M. Lejeune, M. Salvadó, R. Bosch, Juan García, Joaquín Jaén, A. Banham, G. Roncador, C. Montalbán, M. Piris (2005)
Outcome in Hodgkin's Lymphoma Can Be Predicted from the Presence of Accompanying Cytotoxic and Regulatory T Cells
Clinical Cancer Research, 11
P. Antony, C. Paulos, M. Ahmadzadeh, A. Akpinarli, D. Palmer, N. Sato, A. Kaiser, C. Heinrichs, C. Klebanoff, Y. Tagaya, N. Restifo (2006)
Interleukin-2-Dependent Mechanisms of Tolerance and Immunity In Vivo1
The Journal of Immunology, 176
K. Katano, Sadao Suzuki, Y. Ozaki, N. Suzumori, T. Kitaori, M. Sugiura-Ogasawara (2013)
Peripheral natural killer cell activity as a predictor of recurrent pregnancy loss: a large cohort study.
Fertility and sterility, 100 6
H. Fukaura, S. Kent, MATTHEW Pietrusewicz, S. Khoury, H. Weiner, D. Hafler (1996)
Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients.
The Journal of clinical investigation, 98 1
Xiaolei Tang, I. Maričić, N. Purohit, Berge Bakamjian, Lisa Reed-Loisel, Tara Beeston, P. Jensen, Vipin Kumar (2006)
Regulation of Immunity by a Novel Population of Qa-1-Restricted CD8αα+TCRαβ+ T Cells1
The Journal of Immunology, 177
Yijun Carrier, M. Whitters, Joy Miyashiro, T. LaBranche, Hilda Ramón, Stephen Benoit, M. Ryan, S. Keegan, H. Guay, J. Douhan, M. Collins, K. Dunussi-joannopoulos, Q. Medley (2012)
Enhanced GITR/GITRL interactions augment IL‐27 expression and induce IL‐10‐producing Tr‐1 like cells
European Journal of Immunology, 42
A. Hönig, L. Rieger, M. Kapp, M. Sütterlin, J. Dietl, U. Kämmerer (2004)
Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno-fetal tolerance.
Journal of reproductive immunology, 61 2
A. Wakkach, N. Fournier, V. Brun, J. Breittmayer, F. Cottrez, H. Groux (2003)
Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo.
Immunity, 18 5
F. Kanamaru, Pornpan Youngnak, M. Hashiguchi, T. Nishioka, Takeshi Takahashi, S. Sakaguchi, I. Ishikawa, M. Azuma (2004)
Costimulation via Glucocorticoid-Induced TNF Receptor in Both Conventional and CD25+ Regulatory CD4+ T Cells1
The Journal of Immunology, 172
Toshiharu Onodera, M. Jang, Zijin Guo, Mikako Yamasaki, T. Hirata, Zhongbin Bai, N. Tsuji, D. Nagakubo, O. Yoshie, S. Sakaguchi, O. Takikawa, M. Miyasaka (2009)
Constitutive Expression of IDO by Dendritic Cells of Mesenteric Lymph Nodes: Functional Involvement of the CTLA-4/B7 and CCL22/CCR4 Interactions1
The Journal of Immunology, 183
Spencer Liang, Y. Latchman, J. Buhlmann, Michal Tomczak, B. Horwitz, G. Freeman, A. Sharpe (2003)
Regulation of PD‐1, PD‐L1, and PD‐L2 expression during normal and autoimmune responses
European Journal of Immunology, 33
A. Thornton, E. Shevach (1998)
CD4+CD25+ Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production
The Journal of Experimental Medicine, 188
Y. Belkaid, C. Piccirillo, S. Mendez, E. Shevach, D. Sacks (2002)
CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity
Nature, 420
Hori (2003)
Control of regulatory T cell development by the transcription factor Foxp3
Science., 299
Lei Sun, S. Yi, P. O’Connell (2010)
Foxp3 regulates human natural CD4+CD25+ regulatory T‐cell‐mediated suppression of xenogeneic response
Xenotransplantation, 17
T. Tung, Y. Tung (2009)
Experiments on the Developmental Potencies of Blastoderms and Fragments of Teleostean Eggs separated latitudinally
Journal of Zoology, 115
H. Nishikawa, Takuma Kato, Koji Tanida, A. Hiasa, I. Tawara, H. Ikeda, Y. Ikarashi, H. Wakasugi, M. Kronenberg, T. Nakayama, M. Taniguchi, K. Kuribayashi, L. Old, H. Shiku (2003)
CD4+ CD25+ T cells responding to serologically defined autoantigens suppress antitumor immune responses
Proceedings of the National Academy of Sciences of the United States of America, 100
P. Contini, M. Ghio, A. Poggi, G. Filaci, F. Indiveri, S. Ferrone, F. Puppo (2003)
Soluble HLA‐A,‐B,‐C and ‐G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation
European Journal of Immunology, 33
J. Carreras, A. López-Guillermo, B. Fox, L. Colomo, Antonio Martínez, G. Roncador, E. Montserrat, E. Campo, A. Banham (2006)
High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma.
Blood, 108 9
M. Kallikourdis, A. Betz (2007)
Periodic Accumulation of Regulatory T Cells in the Uterus: Preparation for the Implantation of a Semi-Allogeneic Fetus?
PLoS ONE, 2
Susann Pankratz, S. Bittner, A. Herrmann, Michael Schuhmann, T. Ruck, S. Meuth, H. Wiendl (2014)
Human CD4+HLA‐G+ regulatory T cells are potent suppressors of graft‐versus‐host disease in vivo
The FASEB Journal, 28
P. Hsu, B. Santner‐Nanan, S. Joung, M. Peek, R. Nanan (2014)
Expansion of CD4+HLA‐G+ T Cell in Human Pregnancy is Impaired in Pre‐eclampsia
American Journal of Reproductive Immunology, 71
M. Gobert, I. Treilleux, N. Bendriss-Vermare, T. Bachelot, Sophie Goddard-Léon, V. Arfi, C. Biota, A. Doffin, I. Durand, D. Olive, Solène Perez, N. Pasqual, C. Faure, I. Ray-Coquard, A. Puisieux, C. Caux, J. Blay, C. Ménétrier-Caux (2009)
Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome.
Cancer research, 69 5
E. Shevach, A. Thornton (2014)
tTregs, pTregs, and iTregs: similarities and differences
Immunological Reviews, 259
K. Wing, Yasush Onishi, P. Prieto-Martin, Tomoyuki Yamaguchi, M. Miyara, Z. Fehérvári, T. Nomura, S. Sakaguchi (2008)
CTLA-4 Control over Foxp3+ Regulatory T Cell Function
Science, 322
F. Hodi, S. O'Day, D. McDermott, R. Weber, J. Sosman, J. Haanen, R. Gonzalez, C. Robert, D. Schadendorf, Jessica Hassel, W. Akerley, A. Eertwegh, J. Lutzky, P. Lorigan, Julia Vaubel, G. Linette, D. Hogg, C. Ottensmeier, C. Lebbé, C. Peschel, I. Quirt, Joseph Clark, J. Wolchok, J. Weber, Jason Tian, M. Yellin, G. Nichol, A. Hoos, W. Urba (2010)
Improved survival with ipilimumab in patients with metastatic melanoma.
The New England journal of medicine, 363 8
Romy Hoeppli, Dan Wu, Laura Cook, M. Levings (2015)
The Environment of Regulatory T Cell Biology: Cytokines, Metabolites, and the Microbiome
Frontiers in Immunology, 6
G. Betts, E. Jones, S. Junaid, T. El-shanawany, M. Scurr, P. Mizen, Mayur Kumar, Sion Jones, Brian Rees, Geraint Williams, A. Gallimore, A. Godkin (2011)
Suppression of tumour-specific CD4+ T cells by regulatory T cells is associated with progression of human colorectal cancer
Gut, 61
P. Martínez, J. Campo (2017)
Pembrolizumab in recurrent advanced cervical squamous carcinoma.
Immunotherapy, 9 6
C. Ramos, A. Gonçalves, L. Marinho, M. Avelino, V. Saddi, A. Lopes, R. Simões, I. Wastowski (2014)
Analysis of HLA-G gene polymorphism and protein expression in invasive breast ductal carcinoma.
Human immunology, 75 7
M. Jasper, K. Tremellen, S. Robertson (2006)
Primary unexplained infertility is associated with reduced expression of the T-regulatory cell transcription factor Foxp3 in endometrial tissue.
Molecular human reproduction, 12 5
J. Fontenot, J. Rasmussen, L. Williams, James Dooley, A. Farr, A. Rudensky (2005)
Regulatory T cell lineage specification by the forkhead transcription factor foxp3.
Immunity, 22 3
W. Ng, Phillip Duggan, F. Ponchel, G. Matarese, G. Lombardi, A. Edwards, J. Isaacs, R. Lechler (2001)
Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells.
Blood, 98 9
D. Dieckmann, Heidi Plottner, S. Berchtold, T. Berger, G. Schuler (2001)
Ex Vivo Isolation and Characterization of Cd4+Cd25+ T Cells with Regulatory Properties from Human Blood
The Journal of Experimental Medicine, 193
Binqing Fu, Xianchang Li, R. Sun, X. Tong, B. Ling, Z. Tian, Haiming Wei (2012)
Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal–fetal interface
Proceedings of the National Academy of Sciences, 110
Helen Wang, Guangyong Peng, Zhong Guo, E. Shevach, Rong-Fu Wang (2005)
Recognition of a New ARTC1 Peptide Ligand Uniquely Expressed in Tumor Cells by Antigen-Specific CD4+ Regulatory T Cells1
The Journal of Immunology, 174
S. Klein, C. Kretz, P. Krammer, A. Kuhn (2010)
CD127(low/-) and FoxP3(+) expression levels characterize different regulatory T-cell populations in human peripheral blood.
The Journal of investigative dermatology, 130 2
Li-Ping Jin, Qiaoqiao Chen, Tai Zhang, Pei-Fen Guo, Dajin Li (2009)
The CD4+CD25 bright regulatory T cells and CTLA-4 expression in peripheral and decidual lymphocytes are down-regulated in human miscarriage.
Clinical immunology, 133 3
Deyan Hou, A. Muller, Madhav Sharma, J. DuHadaway, Tinku Banerjee, Maribeth Johnson, A. Mellor, G. Prendergast, D. Munn (2007)
Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses.
Cancer research, 67 2
L. Chiossone, P. Vacca, P. Orecchia, D. Croxatto, P. Damonte, S. Astigiano, O. Barbieri, C. Bottino, L. Moretta, M. Mingari (2014)
In vivo generation of decidual natural killer cells from resident hematopoietic progenitors
Haematologica, 99
A. Tafuri, J. Alferink, P. Möller, G. Hämmerling, B. Arnold (1995)
T Cell Awareness of Paternal Alloantigens During Pregnancy
Science, 270
Xiaohong Lin, Maogen Chen, Ya Liu, Zhiyong Guo, Xiaoshun He, D. Brand, S. Zheng (2013)
Advances in distinguishing natural from induced Foxp3(+) regulatory T cells.
International journal of clinical and experimental pathology, 6 2
E. Winger, J. Reed (2011)
Low Circulating CD4+ CD25+ Foxp3+ T Regulatory Cell Levels Predict Miscarriage Risk in Newly Pregnant Women with a History of Failure
American Journal of Reproductive Immunology, 66
F. D’Addio, L. Riella, B. Mfarrej, Lola Chabtini, L. Adams, M. Yeung, H. Yagita, M. Azuma, M. Sayegh, I. Guleria (2011)
The Link between the PDL1 Costimulatory Pathway and Th17 in Fetomaternal Tolerance
The Journal of Immunology, 187
S. Saito, A. Nakashima, T. Shima, Mika Ito (2010)
REVIEW ARTICLE: Th1/Th2/Th17 and Regulatory T‐Cell Paradigm in Pregnancy
American Journal of Reproductive Immunology, 63
G. Darrasse-Jéze, K. Podsypanina (2013)
How Numbers, Nature, and Immune Status of Foxp3+ Regulatory T-Cells Shape the Early Immunological Events in Tumor Development
Frontiers in Immunology, 4
M. Yadav, C. Louvet, Dan Davini, J. Gardner, M. Martínez‐Llordella, Samantha Bailey-bucktrout, Bryan Anthony, F. Sverdrup, R. Head, Daniel Kuster, P. Ruminski, D. Weiss, D. Schack, J. Bluestone (2012)
Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo
The Journal of Experimental Medicine, 209
Thomas Hviid, Sine Hylenius, A. Lindhard, Ole Christiansen (2004)
Association between human leukocyte antigen-G genotype and success of in vitro fertilization and pregnancy outcome.
Tissue antigens, 64 1
J. Heikkinen, M. Möttönen, A. Alanen, O. Lassila (2004)
Phenotypic characterization of regulatory T cells in the human decidua
Clinical & Experimental Immunology, 136
T. Erkers, A. Stikvoort, M. Uhlin (2017)
Lymphocytes in Placental Tissues: Immune Regulation and Translational Possibilities for Immunotherapy
Stem Cells International, 2017
H. Dickinson, S. Ellery, Z. Ireland, Domenic LaRosa, R. Snow, D. Walker (2014)
Creatine supplementation during pregnancy: summary of experimental studies suggesting a treatment to improve fetal and neonatal morbidity and reduce mortality in high-risk human pregnancy
BMC Pregnancy and Childbirth, 14
C. Badoual, S. Hans, J. Rodríguez, S. Peyrard, C. Klein, N. Agueznay, V. Mosseri, O. Laccourreye, P. Bruneval, W. Fridman, D. Brasnu, E. Tartour (2006)
Prognostic Value of Tumor-Infiltrating CD4+ T-Cell Subpopulations in Head and Neck Cancers
Clinical Cancer Research, 12
A. Fukui, Megumi Yokota, Ayano Funamizu, Rika Nakamua, R. Fukuhara, Kenichi Yamada, H. Kimura, A. Fukuyama, Mai Kamoi, Kanji Tanaka, H. Mizunuma (2012)
Changes of NK Cells in Preeclampsia
American Journal of Reproductive Immunology, 67
J. Godin-Ethier, L. Hanafi, C. Piccirillo, R. Lapointe (2011)
Indoleamine 2,3-Dioxygenase Expression in Human Cancers: Clinical and Immunologic Perspectives
Clinical Cancer Research, 17
R. Apps, S. Murphy, R. Fernando, L. Gardner, T. Ahad, A. Moffett (2009)
Human leucocyte antigen (HLA) expression of primary trophoblast cells and placental cell lines, determined using single antigen beads to characterize allotype specificities of anti‐HLA antibodies
Immunology, 127
D. Campbell, M. Koch (2011)
Phenotypical and functional specialization of FOXP3+ regulatory T cells
Nature Reviews Immunology, 11
Hiroyuki Nishimura, M. Nose, H. Hiai, N. Minato, T. Honjo (1999)
Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor.
Immunity, 11 2
A. Habicht, S. Dada, Mollie Jurewicz, B. Fife, H. Yagita, M. Azuma, M. Sayegh, I. Guleria (2007)
A Link between PDL1 and T Regulatory Cells in Fetomaternal Tolerance1
The Journal of Immunology, 179
D. Munn, A. Mellor (2006)
The tumor‐draining lymph node as an immune‐privileged site
Immunological Reviews, 213
Gry Persson, Wenna Melsted, L. Nilsson, T. Hviid (2017)
HLA class Ib in pregnancy and pregnancy-related disorders
Immunogenetics, 69
H. Weiner (2001)
The mucosal milieu creates tolerogenic dendritic cells and TR1 and TH3 regulatory cells
Nature Immunology, 2
U. Liyanage, T. Moore, H. Joo, Yoshiyuki Tanaka, V. Herrmann, G. Doherty, J. Drebin, S. Strasberg, T. Eberlein, P. Goedegebuure, D. Linehan (2002)
Prevalence of Regulatory T Cells Is Increased in Peripheral Blood and Tumor Microenvironment of Patients with Pancreas or Breast Adenocarcinoma1
The Journal of Immunology, 169
T. Shima, Y. Sasaki, Mika Itoh, A. Nakashima, N. Ishii, K. Sugamura, S. Saito (2010)
Regulatory T cells are necessary for implantation and maintenance of early pregnancy but not late pregnancy in allogeneic mice.
Journal of reproductive immunology, 85 2
K. Vangangelt, G. Pelt, C. Engels, H. Putter, G. Liefers, V. Smit, R. Tollenaar, P. Kuppen, W. Mesker (2017)
Prognostic value of tumor–stroma ratio combined with the immune status of tumors in invasive breast carcinoma
Breast Cancer Research and Treatment, 168
Louise Kofod, A. Lindhard, T. Hviid (2018)
Implications of uterine NK cells and regulatory T cells in the endometrium of infertile women.
Human immunology, 79 9
Samantha Drennan, N. Stafford, J. Greenman, V. Green (2013)
Increased frequency and suppressive activity of CD127low/− regulatory T cells in the peripheral circulation of patients with head and neck squamous cell carcinoma are associated with advanced stage and nodal involvement
Immunology, 140
L. Passerini, S. Nunzio, S. Gregori, E. Gambineri, M. Cecconi, M. Seidel, G. Cazzola, L. Perroni, A. Tommasini, S. Vignola, L. Guidi, M. Roncarolo, R. Bacchetta (2011)
Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome
European Journal of Immunology, 41
J. Larkin, V. Chiarion-Sileni, R. Gonzalez, J. Grob, C. Cowey, C. Lao, D. Schadendorf, R. Dummer, M. Smylie, P. Rutkowski, P. Ferrucci, A. Hill, J. Wagstaff, M. Carlino, J. Haanen, M. Maio, I. Márquez-Rodas, G. McArthur, P. Ascierto, G. Long, M. Callahan, M. Postow, M. Postow, K. Grossmann, M. Sznol, B. Dréno, L. Bastholt, A. Yang, L. Rollin, C. Horak, F. Hodi, J. Wolchok, J. Wolchok (2015)
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
The New England journal of medicine, 373 1
Soohyeon Lee, E. Cho, Yeon-Hee Park, J. Ahn, Y. Im (2013)
Prognostic impact of FOXP3 expression in triple-negative breast cancer
Acta Oncologica, 52
Hanyu Zeng, Rong Zhang, Boquan Jin, Lihua Chen (2015)
Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance
Cellular and Molecular Immunology, 12
A. Ladányi, Anita Mohos, B. Somlai, G. Liszkay, K. Gilde, Zsuzsanna Fejős, I. Gaudi, J. Tímár (2010)
FOXP3+ Cell Density in Primary Tumor Has No Prognostic Impact in Patients with Cutaneous Malignant Melanoma
Pathology & Oncology Research, 16
J. Fontenot, M. Gavin, A. Rudensky (2003)
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells
Nature Immunology, 4
K. Milne, M. Köbel, S. Kalloger, Rebecca Barnes, D. Gao, C. Gilks, P. Watson, P. Watson, P. Watson, B. Nelson, B. Nelson, B. Nelson (2009)
Systematic Analysis of Immune Infiltrates in High-Grade Serous Ovarian Cancer Reveals CD20, FoxP3 and TIA-1 as Positive Prognostic Factors
PLoS ONE, 4
Enikő Grozdics, L. Berta, A. Bajnok, G. Veres, I. Ilisz, P. Klivényi, J. Rigó, L. Vécsei, T. Tulassay, G. Toldi (2014)
B7 costimulation and intracellular indoleamine-2,3-dioxygenase (IDO) expression in peripheral blood of healthy pregnant and non-pregnant women
BMC Pregnancy and Childbirth, 14
T. Hviid (2006)
HLA-G in human reproduction: aspects of genetics, function and pregnancy complications.
Human reproduction update, 12 3
D. Keskin, D. Allan, B. Rybalov, Milena Andzelm, Joel Stern, H. Kopcow, L. Koopman, J. Strominger (2007)
TGFβ promotes conversion of CD16+ peripheral blood NK cells into CD16− NK cells with similarities to decidual NK cells
Proceedings of the National Academy of Sciences, 104
R. Gershon, P. Cohen, R. Hencin, S. Liebhaber (1972)
Suppressor T cells.
Journal of immunology, 108 3
Lutao Du, Xiaoyan Xiao, Chuanxin Wang, Xuhua Zhang, N. Zheng, Lili Wang, Xin Zhang, Wei Li, Shun Wang, Zhaogang Dong (2011)
Human leukocyte antigen‐G is closely associated with tumor immune escape in gastric cancer by increasing local regulatory T cells
Cancer Science, 102
N. Seddiki, B. Santner‐Nanan, S. Tangye, S. Alexander, Michael Solomon, S. Lee, R. Nanan, Barbara Groth (2006)
Persistence of naive CD45RA+ regulatory T cells in adult life.
Blood, 107 7
A. Thornton, E. Shevach (2000)
Suppressor Effector Function of CD4+CD25+ Immunoregulatory T Cells Is Antigen Nonspecific
The Journal of Immunology, 164
Jeffrey Weber, S. D’Angelo, D. Minor, F. Hodi, R. Gutzmer, B. Neyns, C. Hoeller, N. Khushalani, Wilson Miller, C. Lao, G. Linette, L. Thomas, P. Lorigan, K. Grossmann, Jessica Hassel, M. Maio, M. Sznol, P. Ascierto, P. Mohr, B. Chmielowski, A. Bryce, I. Svane, J. Grob, Angela Krackhardt, C. Horak, A. Lambert, Arvin Yang, J. Larkin (2015)
Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.
The Lancet. Oncology, 16 4
M. Terme, N. Chaput, B. Combadière, A. Ma, T. Ohteki, L. Zitvogel (2008)
Regulatory T Cells Control Dendritic Cell/NK Cell Cross-Talk in Lymph Nodes at the Steady State by Inhibiting CD4+ Self-Reactive T Cells
The Journal of Immunology, 180
Chris Fellner (2012)
Ipilimumab (yervoy) prolongs survival in advanced melanoma: serious side effects and a hefty price tag may limit its use.
P & T : a peer-reviewed journal for formulary management, 37 9
T. Iversen, L. Engell-Noerregaard, E. Ellebaek, R. Andersen, S. Larsen, J. Bjoern, Claus Zeyher, C. Gouttefangeas, Birthe Thomsen, B. Holm, P. Straten, A. Mellemgaard, M. Andersen, I. Svane (2013)
Long-lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase
Clinical Cancer Research, 20
Yu‐Hwa Huang, A. Zozulya, C. Weidenfeller, N. Schwab, H. Wiendl (2009)
T cell suppression by naturally occurring HLA‐G‐expressing regulatory CD4+ T cells is IL‐10‐dependent and reversible
Journal of Leukocyte Biology, 86
S. Bohling, K. Allison (2008)
Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target
Modern Pathology, 21
H. Groux, A. O’Garra, M. Bigler, M. Rouleau, S. Antonenko, J. Vries, M. Roncarolo (1997)
A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis
Nature, 389
Sakaguchi (1995)
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25)
J Immunol, 155
S. Gnjatic, V. Bronte, L. Brunet, M. Butler, M. Disis, J. Galon, L. Hakansson, B. Hanks, V. Karanikas, S. Khleif, J. Kirkwood, L. Miller, D. Schendel, Isabelle Tanneau, J. Wigginton, L. Butterfield (2017)
Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy
Journal for Immunotherapy of Cancer, 5
Shanshan Zong, Chunqing Li, Chengfeng Luo, X. Zhao, Chunhong Liu, Kai Wang, Wenwen Jia, Mingliang Bai, Minghong Yin, S. Bao, Jie Guo, Jiuhong Kang, T. Duan, Qian Zhou (2016)
Dysregulated expression of IDO may cause unexplained recurrent spontaneous abortion through suppression of trophoblast cell proliferation and migration
Scientific Reports, 6
N. Kobayashi, N. Hiraoka, W. Yamagami, H. Ojima, Y. Kanai, T. Kosuge, A. Nakajima, S. Hirohashi (2007)
FOXP3+ Regulatory T Cells Affect the Development and Progression of Hepatocarcinogenesis
Clinical Cancer Research, 13
L. Moldenhauer, K. Diener, Dougal Thring, M. Brown, J. Hayball, S. Robertson (2009)
Cross-Presentation of Male Seminal Fluid Antigens Elicits T Cell Activation to Initiate the Female Immune Response to Pregnancy1
The Journal of Immunology, 182
R. Khattri, T. Cox, Sue-Ann Yasayko, F. Ramsdell (2017)
Pillars Article: An Essential Role for Scurfin in CD4+CD25+ T Regulatory Cells. Nat. Immunol. 2003. 4: 337-342.
Journal of immunology, 198 3
Chien-Hui Chien, B. Chiang (2017)
Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells
Journal of Biomedical Science, 24
S. Holtan, D. Creedon, P. Haluska, S. Markovic (2009)
Cancer and pregnancy: parallels in growth, invasion, and immune modulation and implications for cancer therapeutic agents.
Mayo Clinic proceedings, 84 11
J. Jacobs, S. Nierkens, C. Figdor, I. Vries, G. Adema (2012)
Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy?
The Lancet. Oncology, 13 1
A. Eggermont, V. Chiarion-Sileni, J. Grob, R. Dummer, J. Wolchok, H. Schmidt, O. Hamid, C. Robert, P. Ascierto, J. Richards, C. Lebbé, V. Ferraresi, M. Smylie, J. Weber, M. Maio, L. Bastholt, L. Mortier, L. Thomas, S. Tahir, A. Hauschild, Jessica Hassel, F. Hodi, C. Taitt, V. Pril, Gaetan Schaetzen, S. Suciu, A. Testori (2016)
Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy.
The New England journal of medicine, 375 19
A. Ishitani, Noriko Sageshima, N. Lee, N. Dorofeeva, K. Hatake, H. Marquardt, D. Geraghty (2003)
Protein Expression and Peptide Binding Suggest Unique and Interacting Functional Roles for HLA-E, F, and G in Maternal-Placental Immune Recognition 1
The Journal of Immunology, 171
G. Freeman, A. Long, Yoshiko Iwai, K. Bourque, T. Chernova, H. Nishimura, L. Fitz, Nelly Malenkovich, Taku Okazaki, M. Byrne, H. Horton, L. Fouser, L. Carter, V. Ling, M. Bowman, B. Carreno, M. Collins, C. Wood, T. Honjo (2000)
Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation
The Journal of Experimental Medicine, 192
M. Solders, L. Gorchs, T. Erkers, Anna-Carin Lundell, S. Nava, S. Gidlöf, E. Tiblad, I. Magalhaes, H. Kaipe (2017)
MAIT cells accumulate in placental intervillous space and display a highly cytotoxic phenotype upon bacterial stimulation
Scientific Reports, 7
Bin Shang, Yao Liu, Shu-juan Jiang, Yi Liu (2015)
Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis
Scientific Reports, 5
F. Ghiringhelli, C. Ménard, M. Terme, C. Flament, J. Taieb, N. Chaput, P. Puig, S. Novault, B. Escudier, É. Vivier, A. Lecesne, C. Robert, J. Blay, J. Bernard, S. Caillat-Zucman, A. Freitas, T. Tursz, O. Wagner-Ballon, C. Capron, W. Vainchencker, F. Martin, L. Zitvogel (2005)
CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner
The Journal of Experimental Medicine, 202
T. Kieffer, M. Faas, S. Scherjon, J. Prins (2017)
Pregnancy persistently affects memory T cell populations.
Journal of reproductive immunology, 119
Romy Hoeppli, K. MacDonald, M. Levings, Laura Cook (2016)
How antigen specificity directs regulatory T‐cell function: self, foreign and engineered specificity
HLA, 88
Niclas Jonzén, Andreas Lindén, Torbjørn Ergon, E. Knudsen, J. Vik, Diego Rubolini, D. Piacentini, Christian Brinch, Fernando Spina, Lennart Karlsson, Martin Stervander, Arne Andersson, Jonas Waldenström, A. Lehikoinen, Erik Edvardsen, Rune Solvang, N. Stenseth (2003)
Supporting Online Material
M. Jordan, A. Boesteanu, A. Reed, Andria Petrone, Andrea Holenbeck, M. Lerman, A. Naji, A. Caton (2001)
Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide
Nature Immunology, 2
S. Robertson, Leigh Guerin, L. Moldenhauer, J. Hayball (2009)
Activating T regulatory cells for tolerance in early pregnancy - the contribution of seminal fluid.
Journal of reproductive immunology, 83 1-2
Leigh Guerin, J. Prins, S. Robertson (2009)
Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment?
Human Reproduction Update, 15
E. Kruijf, A. Sajet, J. Nes, Russ Natanov, H. Putter, V. Smit, G. Liefers, P. Elsen, C. Velde, P. Kuppen (2010)
HLA-E and HLA-G Expression in Classical HLA Class I-Negative Tumors Is of Prognostic Value for Clinical Outcome of Early Breast Cancer Patients
The Journal of Immunology, 185
S. Sakaguchi, N. Sakaguchi, M. Asano, M. Itoh, M. Toda (1995)
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
Journal of immunology, 155 3
K. Loser, J. Apelt, M. Voskort, M. Mohaupt, S. Balkow, T. Schwarz, S. Grabbe, S. Beissert (2007)
IL-10 Controls Ultraviolet-Induced Carcinogenesis in Mice1
The Journal of Immunology, 179
S. Sakaguchi (2005)
Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self
Nature Immunology, 6
A. Tanaka, S. Sakaguchi (2016)
Regulatory T cells in cancer immunotherapy
Cell Research, 27
M. Fransson, Elena Piras, J. Burman, B. Nilsson, M. Essand, B. Lu, R. Harris, P. Magnusson, E. Brittebo, A. Loskog (2012)
CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery
Journal of Neuroinflammation, 9
J. Fumet, N. Isambert, A. Hervieu, S. Zanetta, Jean-Florian Guion, A. Hennequin, E. Rederstorff, A. Bertaut, F. Ghiringhelli (2018)
Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer
ESMO Open, 3
Georgina Long, Reinhard Dummer, O. Hamid, Thomas Gajewski, Christian Caglevic, Stéphane Dalle, A. Arance, M. Carlino, Jean-Jacques Grob, Tae Kim, Lev Demidov, Caroline Robert, J. Larkin, James Anderson, J. Maleski, Mark Jones, S. Diede, Tara Mitchell (2018)
Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: Results of the phase 3 ECHO-301/KEYNOTE-252 study.
Journal of Clinical Oncology, 36
Shawn Mahmud, Luke Manlove, Heather Schmitz, Yan Xing, Yanyan Wang, David Owen, J. Schenkel, J. Boomer, Jonathan Green, H. Yagita, H. Chi, K. Hogquist, M. Farrar (2014)
Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation
Nature immunology, 15
Amal Ephrem, A. Epstein, G. Stephens, A. Thornton, D. Glass, E. Shevach (2013)
Modulation of Treg cells/T effector function by GITR signaling is context–dependent
European Journal of Immunology, 43
A. Bayer, Joon Lee, A. Barrera, C. Surh, T. Malek (2008)
A Function for IL-7R for CD4+CD25+Foxp3+ T Regulatory Cells1
The Journal of Immunology, 181
M. Levings, R. Bacchetta, Ute Schulz, M. Roncarolo (2002)
The Role of IL-10 and TGF-β in the Differentiation and Effector Function of T Regulatory Cells
International Archives of Allergy and Immunology, 129
Yong-Chen Lu, P. Robbins (2016)
Cancer immunotherapy targeting neoantigens.
Seminars in immunology, 28 1
D. Somerset, Yong Zheng, M. Kilby, D. Sansom, M. Drayson (2004)
Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T‐cell subset
Immunology, 112
H. Weiner (2001)
Induction and mechanism of action of transforming growth factor‐β‐secreting Th3 regulatory cells
Immunological Reviews, 182
A. Horuzsko, F. Lenfant, D. Munn, A. Mellor (2001)
Maturation of antigen-presenting cells is compromised in HLA-G transgenic mice.
International immunology, 13 3
Gisela Silva, T. Silva, R. Duarte, N. Neto, H. Carrara, E. Donadi, M. Gonçalves, E. Soares, C. Soares (2013)
Expression of the Classical and Nonclassical HLA Molecules in Breast Cancer
International Journal of Breast Cancer, 2013
L. Antonioli, P. Pacher, E. Vizi, G. Haskó (2013)
CD39 and CD73 in immunity and inflammation.
Trends in molecular medicine, 19 6
N. Hiraoka, K. Onozato, T. Kosuge, S. Hirohashi (2006)
Prevalence of FOXP3+ Regulatory T Cells Increases During the Progression of Pancreatic Ductal Adenocarcinoma and Its Premalignant Lesions
Clinical Cancer Research, 12
Yating Yu, Xinbo Ma, R. Gong, Jian-Yang Zhu, Lihua Wei, Jinguang Yao (2018)
Recent advances in CD8+ regulatory T cell research.
Oncology letters, 15 6
M. Mandapathil, M. Szczepański, M. Szajnik, Jin-ping Ren, E. Jackson, Jonas Johnson, E. Gorelik, S. Lang, T. Whiteside (2010)
Adenosine and Prostaglandin E2 Cooperate in the Suppression of Immune Responses Mediated by Adaptive Regulatory T Cells*
The Journal of Biological Chemistry, 285
C. Asseman, S. Mauze, M. Leach, R. Coffman, F. Powrie (1999)
An Essential Role for Interleukin 10 in the Function of Regulatory T Cells That Inhibit Intestinal Inflammation
The Journal of Experimental Medicine, 190
H. Jonuleit, E. Schmitt, M. Stassen, A. Tuettenberg, J. Knop, A. Enk (2001)
Identification and Functional Characterization of Human Cd4+Cd25+ T Cells with Regulatory Properties Isolated from Peripheral Blood
The Journal of Experimental Medicine, 193
Youhai Chen, V. Kuchroo, J. Inobe, D. Hafler, H. Weiner (1994)
Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis.
Science, 265 5176
Francisco Cabestre, Philippe Moreau, B. Riteau, E. Ibrahim, C. Danff, Jean Dausset, N. Rouas-Freiss, E. Carosella, Pascale Paul (1999)
HLA-G expression in human melanoma cells: protection from NK cytolysis.
Journal of reproductive immunology, 43 2
Ting-mei Chen, G. Darrasse-Jéze, A. Bergot, T. Courau, G. Churlaud, K. Valdivia, J. Strominger, M. Ruocco, G. Chaouat, D. Klatzmann (2013)
Self-Specific Memory Regulatory T Cells Protect Embryos at Implantation in Mice
The Journal of Immunology, 191
R. Pacholczyk, P. Kraj, L. Ignatowicz (2002)
Peptide Specificity of Thymic Selection of CD4+CD25+ T Cells
The Journal of Immunology, 168
R. Heitmann, R. Weitzel, Yanling Feng, J. Segars, J. Tisdale, E. Wolff (2017)
Maternal T Regulatory Cell Depletion Impairs Embryo Implantation Which Can Be Corrected With Adoptive T Regulatory Cell Transfer
Reproductive Sciences, 24
R. Ramhorst, L. Fraccaroli, P. Aldo, A. Alvero, I. Cardenas, C. Leirós, G. Mor (2012)
Modulation and Recruitment of Inducible Regulatory T Cells by First Trimester Trophoblast Cells
American Journal of Reproductive Immunology, 67
Yoshiko Iwai, S. Terawaki, T. Honjo (2004)
PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells.
International immunology, 17 2
Su Liu, L. Diao, Chunyu Huang, Yuye Li, Y. Zeng, J. Kwak‐Kim (2017)
The role of decidual immune cells on human pregnancy.
Journal of reproductive immunology, 124
J. Shimizu, S. Yamazaki, Takeshi Takahashi, Y. Ishida, S. Sakaguchi (2002)
Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance
Nature Immunology, 3
Shuping Zhang, Meng Wu, F. Wang (2018)
Immune regulation by CD8+ Treg cells: novel possibilities for anticancer immunotherapy
Cellular & Molecular Immunology, 15
T. Curiel, G. Coukos, L. Zou, Xavier Alvarez, P. Cheng, P. Mottram, Melina Evdemon-Hogan, J. Conejo-Garcia, Lin Zhang, M. Burow, Yun Zhu, Shuang Wei, Ilona Kryczek, B. Daniel, Alan Gordon, L. Myers, A. Lackner, M. Disis, K. Knutson, Lieping Chen, W. Zou (2004)
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival
Nature Medicine, 10
I. Kosten, T. Rustemeyer (2015)
Generation, subsets and functions of inducible regulatory T cells.
Anti-inflammatory & anti-allergy agents in medicinal chemistry, 13 3
C. Robert, J. Schachter, G. Long, A. Arance, J. Grob, L. Mortier, A. Daud, M. Carlino, C. McNeil, M. Lotem, J. Larkin, P. Lorigan, B. Neyns, C. Blank, O. Hamid, C. Mateus, R. Shapira-Frommer, M. Kosh, Honghong Zhou, N. Ibrahim, S. Ebbinghaus, A. Ribas (2015)
Pembrolizumab versus Ipilimumab in Advanced Melanoma.
The New England journal of medicine, 372 26
Nathan West, S. Kost, Spencer Martin, K. Milne, R. deLeeuw, B. Nelson, P. Watson, P. Watson (2012)
Tumour-infiltrating FOXP3+ lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer
British Journal of Cancer, 108
W. Fridman, F. Pagès, C. Sautès-Fridman, J. Galon (2012)
The immune contexture in human tumours: impact on clinical outcome
Nature Reviews Cancer, 12
Chao Wang, Jiahuan Chen, Qian-fei Zhang, Wang Li, Shengbo Zhang, Yanjie Xu, F. Wang, Bing Zhang, Yan Zhang, Wei-Qiang Gao (2018)
Elimination of CD4lowHLA-G+ T cells overcomes castration-resistance in prostate cancer therapy
Cell Research, 28
S. Antonia, S. Goldberg, A. Balmanoukian, J. Chaft, R. Sanborn, A. Gupta, R. Narwal, K. Steele, Y. Gu, J. Karakunnel, N. Rizvi (2016)
Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study.
The Lancet. Oncology, 17 3
Gaynor Bates, S. Fox, Cheng Han, R. Leek, J. García, A. Harris, A. Banham (2006)
Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 24 34
M. Andersen (2012)
The specific targeting of immune regulation: T-cell responses against Indoleamine 2,3-dioxygenase
Cancer Immunology, Immunotherapy : CII, 61
A. Schumacher, P. Wafula, A. Teles, Tarek El-Mousleh, Nadja Linzke, M. Zenclussen, Stefanie Langwisch, K. Heinze, I. Wollenberg, P. Casalis, H. Volk, S. Fest, A. Zenclussen (2012)
Blockage of Heme Oxygenase-1 Abrogates the Protective Effect of Regulatory T Cells on Murine Pregnancy and Promotes the Maturation of Dendritic Cells
PLoS ONE, 7
S. Ronchetti, Erika Ricci, M. Petrillo, L. Cari, G. Migliorati, G. Nocentini, C. Riccardi (2015)
Glucocorticoid-Induced Tumour Necrosis Factor Receptor-Related Protein: A Key Marker of Functional Regulatory T Cells
Journal of Immunology Research, 2015
S. Miyazaki, H. Tsuda, M. Sakai, S. Hori, Y. Sasaki, T. Futatani, T. Miyawaki, S. Saito (2003)
Predominance of Th2‐promoting dendritic cells in early human pregnancy decidua
Journal of Leukocyte Biology, 74
SA Mahmud, LS Manlove, HM Schmitz, Y Xing, Y Wang, DL Owen (2014)
Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation
Nat Immunol, 15
L. Demir, S. Yiğit, H. Ellidokuz, Ç. Erten, I. Somalı, Y. Kucukzeybek, A. Alacacıoğlu, S. Çokmert, A. Can, M. Akyol, A. Dirican, V. Bayoğlu, A. Sari, M. Tarhan (2013)
Predictive and prognostic factors in locally advanced breast cancer: effect of intratumoral FOXP3+ Tregs
Clinical & Experimental Metastasis, 30
M. Overman, S. Lonardi, K. Wong, H. Lenz, F. Gelsomino, M. Aglietta, M. Morse, E. Cutsem, R. McDermott, A. Hill, M. Sawyer, A. Hendlisz, Bart, Neyns, M. Svrcek, R. Moss, J. Ledeine, Z. Cao, S. Kamble, S. Kopetz, T. André (2018)
Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 36 8
L. Benevides, C. Cardoso, D. Tiezzi, H. Marana, J. Andrade, J. Silva (2013)
Enrichment of regulatory T cells in invasive breast tumor correlates with the upregulation of IL‐17A expression and invasiveness of the tumor
European Journal of Immunology, 43
A. Moffett-King (2002)
Natural killer cells and pregnancy
Nature Reviews Immunology, 2
(2004)
T cells + regulatory CD4 + CD25 TNF receptor in both conventional and costimulation via Glucocorticoid-induced Sakaguchi
D. Leach, M. Krummel, J. Allison (1996)
Enhancement of Antitumor Immunity by CTLA-4 Blockade
Science, 271

Publisher: Unpaywall
ISSN: 1664-3224
DOI: 10.3389/fimmu.2019.00911
Publisher site: See Article on Publisher Site

Abstract

REVIEW published: 08 May 2019 doi: 10.3389/ﬁmmu.2019.00911 The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer Nanna Jørgensen, Gry Persson and Thomas Vauvert F. Hviid* Department of Clinical Biochemistry, Centre for Immune Regulation and Reproductive Immunology (CIRRI), The ReproHealth Consortium ZUH, Zealand University Hospital, and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Regulatory T cells, a subpopulation of suppressive T cells, are potent mediators of self-tolerance and essential for the suppression of triggered immune responses. The immune modulating capacity of these cells play a major role in both transplantation, autoimmune disease, allergy, cancer and pregnancy. During pregnancy, low numbers of regulatory T cells are associated with pregnancy failure and pregnancy complications such as pre-eclampsia. On the other hand, in cancer, low numbers of immunosuppressive T cells are correlated with better prognosis. Hence, maternal immune tolerance toward the fetus during pregnancy and the escape from host immunosurveillance by cancer seem to be based on similar immunological mechanisms Edited by: being highly dependent on the balance between immune activation and suppression. Djordje Miljkovic, As regulatory T cells hold a crucial role in several biological processes, they may also University of Belgrade, Serbia be promising subjects for therapeutic use. Especially in the ﬁeld of cancer, cell therapy Reviewed by: Carlo Riccardi, and checkpoint inhibitors have demonstrated that immune-based therapies have a University of Perugia, Italy very promising potential in treatment of human malignancies. However, these therapies Katarina Mirjacic Martinovic, Institute of Oncology and Radiology of are often accompanied by adverse autoimmune side effects. Therefore, expanding Serbia, Serbia the knowledge to recognize the complexities of immune regulation pathways shared *Correspondence: across different immunological scenarios is extremely important in order to improve and Thomas Vauvert F. Hviid develop new strategies for immune-based therapy. The intent of this review is to highlight [email protected] the functional characteristics of regulatory T cells in the context of mechanisms of Specialty section: immune regulation in pregnancy and cancer, and how manipulation of these mechanisms This article was submitted to potentially may improve therapeutic options. Immunological Tolerance and Regulation, Keywords: regulatory T cells, immune tolerance, cancer, immunotherapy, pregnancy, preeclampsia, HLA class Ib a section of the journal Frontiers in Immunology Received: 15 November 2018 INTRODUCTION Accepted: 09 April 2019 Published: 08 May 2019 Regulatory T cells (Tregs) constitute a dynamic and diverse T cell population composed of several Citation: subsets distinguished by phenotypic and functional characteristics. With their immunosuppressive Jørgensen N, Persson G and properties, Tregs are central to the maintenance of immune homeostasis. They are implicated Hviid TVF (2019) The Tolerogenic in critical immunoregulatory functions in several physiological conditions such as inﬂammatory Function of Regulatory T Cells in responses, tissue repair, and reproduction. Furthermore, Tregs also play an important role in the Pregnancy and Cancer. pathophysiological immune tolerance induced by tumors (1–4). Hence, selective immunological Front. Immunol. 10:911. doi: 10.3389/ﬁmmu.2019.00911 tolerance is essential during any of these processes, and the mechanisms by which immune Frontiers in Immunology | www.frontiersin.org 1 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer tolerance is sustained by Tregs might be similar. Some of the mechanisms responsible for induction of maternal immune tolerance during pregnancy may be the same as those involved in controlling an inﬂammatory response from not exaggerating beyond control, and furthermore the same mechanisms that may provide a pro-tumorigenic environment which allows cancer development. The role of Tregs is somewhat opposing in relation to a role in protecting the body and preventing disease development. Tregs must allow protective immune responses against pathogens and tumors, but simultaneously prevent inﬂammatory diseases by restraining aberrant responses to self and innocuous antigens with pregnancy as a borderline condition, where Tregs contribute to the establishment of active immune tolerance toward the fetus (Figure 1). The similarities between reproductive biology and cancer development in terms of immunology is not that implausible. During pregnancy, the formation of the placenta involves the invasion of the semi-allogeneic fetal trophoblast cells into the maternal tissue for anchoring and vascular adaptions, such as formation of spiral arteries providing nutritional support for the growing fetus. The maternal immune system has to allow this invasion of partly foreign cells to ensure a successful pregnancy. Thus, cancer cells and cells of the developing placenta both share the capacity to invade normal tissue and create a microenvironment that support immunologic privilege and angiogenesis (Figure 1). The proliferation and migration of cancer cells at a distant site mediated in part by modulation of a tolerogenic immune response in the tumor microenvironment may be compared to the situation in pregnancy, in which the developing placenta invades the uterus and a semi-allogenic fetus escapes rejection from the maternal immune system (5– 7). A prominent hypothesis states that the failure to establish immune tolerance during pregnancy may lead to pregnancy complications or pregnancy loss. However, this may indicate that it should be possible to exploit the same mechanisms responsible for immune regulation during pregnancy in treatment of cancer and to reject cancer cells by immunological mechanisms (5). Finally, it is important to remember that immunomodulation and immunosuppression during pregnancy are physiological FIGURE 1 | Immune mechanisms during pregnancy and cancer development. mechanisms but in cases of cancer they are pathological and in Although immunomodulation during pregnancy is a physiological process and most cases unfavorable. in cases of cancer a pathophysiological process, there are a number of similarities in cellular and molecular mechanisms at the feto-maternal interface The function of Tregs as potent anti-inﬂammatory cells and in the tumor microenvironment. Tumors and fetuses seem to exploit some has led to considerable interest in their therapeutic potential. of the same immunomodulating mechanisms. Formation of the placenta In cancer, there has been much progress within the ﬁeld of during pregnancy involves invasion of fetal trophoblast cells into the maternal immunotherapy within the last decade. Especially, cancer therapy tissue for anchoring and vascular adaptions. In cancer, local invasion into by inhibition of negative immune regulation is already used neighboring tissue is essential for manifestation of malignant growth and the ﬁrst stage in development of secondary tumors or metastases. Furthermore, in the clinic. Manipulation and propagation of Tregs and their several immune cells are present both at the feto-maternal interface and in the therapeutic application is a promising approach in order to reach tumor microenvironment, here with malignant melanoma as an example. There a clinical beneﬁt for aﬀected patients (8–10). is increasing evidence that regulatory T cells play important roles both in As brieﬂy mentioned above, while pregnancy is a physiological cancer and in reproduction. [Illustration partly inspired by Holtan et al. (5)]. process in which the presence of Treg cells is favorable, cancer is a pathophysiological scenario in which the suppression of a potential anti-tumor response is undesirable. However, as will This highlights the importance of broadening our understanding be discussed in later sections, this distinction is not always of the function of Treg cells across diﬀerent physiological obvious, and in some cancer settings, the presence of Treg and pathophysiological settings, such as pregnancy, pregnancy cells and thus the control of the inﬂammatory environment can complications, and cancer, in order to develop and oﬀer the probably be advantageous seen from an anti-tumor perspective. right therapeutic treatment. This review provides an overview Frontiers in Immunology | www.frontiersin.org 2 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer of current knowledge on the tolerogenic function of Tregs in Regulatory T Cell Subsets immunological mechanisms during pregnancy and cancer, and Tregs are found throughout the body, where they modulate in relation to possible therapeutic intervention of both human activities of cellular components of both the innate and adaptive malignancies and reproduction. immune system. CD4 Tregs can be divided into distinct subsets according to unique functional and homeostatic properties (Figure 2). FoxP3 Tregs originating from the thymus, where they have diﬀerentiated during T cell ontogenesis, are referred REGULATORY T CELLS to as natural or thymic (t) Tregs, and Tregs developed in the Regulatory T cells are a T lymphocyte population with periphery or in vitro from conventional CD4 T cells are referred immune suppressive properties responsible for maintaining to as peripheral or induced (i) Tregs (30, 31). Furthermore, there antigen-speciﬁc T cell tolerance. Tregs comprise both are two phenotypically distinct immunosuppressive subtypes + + + CD4 and CD8 subtypes. Whereas, CD4 Treg cells of the iTregs, namely the IL-10 producing T regulatory type have been extensively studied, lack of clear markers to 1 (Tr1) cells and the TGF-β-producing Th3 cells (32, 33). It + + distinguish CD8 Tregs from conventional CD8 T cells remains to be determined, whether the diﬀerent subsets of Tregs has led to unsatisfactory characterization of origin, function belong to unique cell lineages, or whether they only reﬂect the and phenotype (11, 12). Therefore, this review will focus plasticity of the Treg population and represent an altered state mainly on CD4 regulatory T cell subsets, and “Treg” or of diﬀerentiation (34). Furthermore, it is debated, whether iTregs “regulatory T cell” will refer to CD4 regulatory T cells, unless can arise from any conventional T cell or from a pre-committed stated otherwise. cell lineage (35). + + Normally, CD4 Tregs constitute 5–10% of the total CD4 Both tymus-derived tTregs and peripheral iTregs T cell population and are derived from thymic precursors (13). are characterized by high expression of CD25, FoxP3, Regulatory T cells where ﬁrst described in 1972, where Gershon cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and et al. showed that T cells were capable of suppressing the antigen- glucocorticoid-induced tumor necrosis factor-related receptor induced response of other T cells directly without the mediation (GITR), but iTregs have been shown to express reduced levels of of B cells and their production of antibodies (14). However, it was programmed cell death protein 1 (PD-1), CD73, the transcription not until 1995 that Tregs were identiﬁed as a specialized CD4 factor Helios and the surface antigen neutropilin-1 (Nrp1) (36). T cell population expressing CD25 (15). Subsequently, several Both Helios and Nrp1 have been suggested as markers for + + in vitro studies showed that CD4 CD25 T cells represent distinguishing between tTregs and iTregs, but the speciﬁcity a distinct lineage of naturally anergic and suppressive cells of these markers is a current matter of debate (36–39). Mice (16, 17). The original studies on characterization of Tregs studies have suggested that GITR is involved in the generation were performed in mice. However, in 2001 a T cell population and maturation of FoxP3 tTregs and Tr1-like cells (40, 41). with identical immunosuppressive properties was identiﬁed in Furthermore, it has been suggested that GITR is a marker of humans (18–21). In 2003, the transcription factor forkhead active Tregs (42). In addition to the above mentioned markers, box protein P3 (FoxP3) was identiﬁed as a potent marker for expression of the ATP-degrading enzymes CD39 and CD73 on Tregs in several mouse studies. FoxP3 deﬁciency caused a fatal the surface of Tregs have been increasingly used as markers of lymphoproliferative disease demonstrating that the transcription Tregs and might contribute to the suppressive activity together factor was essential for development of Tregs and for their with expression of the immunoglobulin-like transmembrane immunosuppressive function (22–24). The requirement of FoxP3 protein LAG3 (Figure 3) (43–46). + + expression for immunosuppression was later demonstrated in Thymic CD4 CD25 tTregs are developed in the thymus from CD4 precursors. Development of tTregs or conventional humans (25). + + Based on these discoveries, expression of CD25 on the cell CD4 T cell populations from the CD4 precursor depends surface and presence of the intracellular transcription factor on the aﬃnity of the T cell receptor (TCR) for self-antigens: low aﬃnity leads to positive selection of conventional CD4 T FoxP3 became the key characteristics of the Treg population. cells, whereas medium aﬃnity interactions with thymic epithelial The mutual expression of these markers is commonly used for + + cells lead to development of CD4 CD25 tTregs (47–49). identiﬁcation of Tregs in experimental settings. Conversely, some Immunosuppression by tTregs require activation via their TCR. studies suggest a lack of correlation between CD25 and FoxP3 in When activated, the suppressor eﬀector function is independent human and mice CD4 T cells (24, 26). Alternatively, Liu et al. of antigen-speciﬁcity. Conversely, inhibition of the eﬀector T found that low expression of CD127 serves as a good biomarker (Teﬀ) cell population is mainly depending on cell contact and for human Tregs together with CD25 expression (26), although independent of suppressive cytokines (18, 50). The result of tTreg other studies have not been able to ﬁnd a clear correlation lo mediated immune regulation is reduced number of Teﬀ cells and between CD127 and FoxP3 expression (27). In addition, several + − − altered activity and traﬃcking pattern of activated Teﬀ cells (37). sub-populations of CD4 CD25 FoxP3 Tregs have also been identiﬁed (28). Hence, the most speciﬁc marker still remains In vitro or in vivo induced iTregs can be diﬀerentiated from naïve CD4 T cells in response to antigen, CD28, TGF-β and a matter of debate. Nevertheless, as expression of FoxP3 has IL-2 stimulation, and mediate their suppressive activity mainly been shown to correlate with suppressor activity irrespectively of via secretion of cytokines such as IL-10 and TGF-β that reduce CD25 expression many consider FoxP3 as the most speciﬁc Treg the capacity of dendritic cells (DCs) to present antigen (37). marker (29). Frontiers in Immunology | www.frontiersin.org 3 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer + + FIGURE 2 | Characteristics of CD4 regulatory T cell subsets. Different subsets of CD4 regulatory T (Treg) cells exist and play a role in the establishment of tolerance in different physiological and pathophysiological settings. Thymic (t)Tregs and HLA-G Tregs are developed in the thymus in response to self-antigen, whereas induced (i)Tregs, Tr1 cells and Th3 cells are developed in the periphery in response to antigen presentation and cytokines. Natural Treg and iTregs are + − − characterized by CD25 and FoxP3 expression, while HLA-G Tregs, Tr1, and Th3 cells are CD25 FoxP3 , although controversies do exist (see the text for details). The thymus-derived Treg cells mediate their effect mainly through cell contact. In contrast, immune suppression by peripheral induced iTreg, Tr1, and Th3 cells are mediated mainly via secretion of the anti-inﬂammatory cytokines TGF-β and IL-10. As for the iTregs, the peripheral Tr1 and Th3 subsets are also the suppressive eﬀect of HLA-G expression was conﬁrmed + + + induced in the periphery from the conventional CD4 T cells. by neutralization of HLA-G on CD4 HLA-G cells, which In contrast to tTregs and iTregs, expression of CD25 and FoxP3 reduced their suppressive capacity. The cells were, however, not in Tr1 and Th3 cells are controversial (51–53). Tr1 and Th3 expressing CD25 and FoxP3, like previously described Tregs. have been identiﬁed as FoxP3- and CD25-negative, although it When comparing the properties and molecular characteristics + + + + + seems that expression of both markers can be upregulated in of CD4 HLA-G cells and CD4 CD25 FoxP3 cells, there response to activation (53, 54). The Tr1 cells were ﬁrst described is a clear distinction between the phenotype and the cytokine by Groux et al. (55), who found that Tr1 cells are activated by proﬁle of the two cell populations (62). The suppressive function + + + IL-10 and suppress the proliferation of CD4 cells in response to of CD4 HLA-G cells is mediated mainly by secretion of antigen (55). Presence of IFN-α further enhances IL-10-mediated soluble HLA-G and high levels of IL-10 and IL-35, while + + + induction of Tr1 activation and diﬀerentiation (56). The Tr1 CD4 CD25 FoxP3 cells seems to work mainly in a cell-contact + + cells constitute a low proliferating subset that produces high dependent manner. Furthermore, CD4 HLA-G cells are clearly levels of IL-10, low levels of TGF-β and marginal or no IL-2 and distinct from Tr1 cells as they do not require the presence IL-4 (55, 57). Th3 cells are activated upon antigen stimulation of other cell types (63). The identiﬁcation of a novel T cell (58). However, TGF-β also promote the induction of Th3 cells population with regulatory properties expressing HLA-G on the from CD4 T cells, which can be further enhanced by the surface has led to the notion of a new subset belonging to the presence of IL-10 and IL-4 (32). When active, the Th3 cells have repertoire of suppressor T cells (64). As these cells have a similar + + + suppressive properties for Th1 and Th2 cells through secretion of function as CD4 CD25 FoxP3 Tregs, their role in peripheral TGF-β (59, 60). immune regulation is increasingly recognized. However, whether A new subset of regulatory T cells have emerged during the they should be identiﬁed as traditional regulatory T cells as the recent years deﬁned by expression of the immunosuppressive classical Tregs is somehow controversial. Human Leukocyte Antigen (HLA) molecule HLA-G (Figure 2). No universal agreement on which factors that can be used In 2007, Feger et al. identiﬁed HLA-G T cells among CD4 and to diﬀerentiate tTregs from iTregs seems to exist. Moreover, CD8 single-positive cells in the peripheral blood and thymus it is important to note that most studies have used shared from healthy individuals (61). The cell population showed markers such as FoxP3, CD25, and CD127 for identiﬁcation of reduced proliferation to allogeneic and polyclonal stimuli and Treg cells, thus do not diﬀerentiate between tTregs and iTregs, Frontiers in Immunology | www.frontiersin.org 4 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer FIGURE 3 | Schematic overview of similarities in Treg function in central tolerance, fetal tolerance, and cancer tolerance. Tolerance play an important role in both fetal and cancer tolerance. Tregs are developed by presentation of antigens of fetal (fAg) or tumor (tAg) origin. Many tumor cells and fetal extravillous trophoblast (EVT) cells have both diminished or no expression of MHC class II and classical MHC class I molecules. Instead, the EVT cells and some cancer cells express HLA class Ib molecules, e.g., the immune modulatory non-classical HLA-G. HLA-G is able to protect fetal and tumor cells from NK cell lysis, as well as according to a few studies to induce Treg formation. Fetal EVTs and tumor cells are also able to contribute to Treg homeostasis by inhibiting effector T cell activation and proliferation through PD-L1/PD-1 and indoleamine-2,3-dioxygenase (IDO) expression. Decidual (d)NK cells further contribute by inhibiting Th17 responses by IFN-γ expression. Fetal EVTs also express cytokines, e.g., IL-10 and TGF-β that induce Treg development. Tregs limit Teff cells and promote their own proliferation and survival through direct engagement with Teff cells, e.g., via PD-L1/PD-1, by the conversion of ATP to Adenosine (Ado) and cytokine secretion. and by that deﬁnition also exclude any immunosuppressive THE ROLE OF TREGS IN CANCER − + FoxP3 T cells, such as the Tr1, Th3, and HLA-G Tregs. The progression of cancer is controlled by a complex biologic The following section will focus on studies using FoxP3, system that is highly dependent on interaction between the CD25, and CD127, and the term “Treg” will therefore refer to malignant cells and the surrounding tumor microenvironment regulatory CD4 T cells regardless of origin, unless speciﬁcally comprising the immune cells. Various types of immune cells stated otherwise. Frontiers in Immunology | www.frontiersin.org 5 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer can inﬁltrate the tumor and may inﬂuence tumors diﬀerently Mechanisms of Treg-Mediated depending on their histological and molecular type, their stage, Immunosuppression in Cancer the microenvironment of the organ in which they occur, and Several mechanisms contribute to the accumulation of Tregs the nature of the tumor (Figure 1) (65). Immune eﬀector within neoplastic lesions including increased inﬁltration, cells can detect and destroy cancer cells preventing tumor local expansion, survival advantage, and development from formation by means of both the innate and adaptive immune conventional CD4 cells (30). All of these mediated through compartments. However, the anti-tumor activity of the immune signaling with other cells and through diﬀerent signaling cells are often downregulated by tumor-derived signals leading molecules (Figure 3). to immune escape. A large number of preclinical models Studies on mice deﬁcient of key markers of Tregs, including have demonstrated the inﬂuence of Tregs in development and IL-10, CTLA-4, GITR, or PD-1 that develop severe immune- progression of several types of malignancies, and Tregs are related disorders indicate that these molecules are crucial for generally believed to be a signiﬁcant contributor to tumor Treg function in a cancer setting. The CTLA-4 receptor is a immune escape (66, 67). A widely accepted hypothesis is that negative regulator of T cell responses functioning as an immune recruitment of tumor-inﬁltrating Tregs with immunosuppressive checkpoint. Leach et al. was the ﬁrst to show that blockades of properties enable the malignant cells to evade the host immune the inhibitory signals of CTLA-4 enhance antitumor immunity response (68). in mice (97). Proof that this was also the case in humans came Increased numbers of tumor-inﬁltrating Tregs have in 2003 in a clinical investigation, where CTLA-4 blockade been demonstrated in patients with ovarian (69), liver (70), increased tumor immunity in some previously vaccinated melanoma (68), gastric, and esophageal cancer (71), in melanoma and ovarian carcinoma patients (98). Much research chronic lymphocytic leukemia (72), and in breast cancer, have been performed on the mechanism of antitumor immunity where it is associated with a more aggressive phenotype elicited by CTLA-4 blockade and one study has shown that (73). The same is seen in gastric and esophageal cancers, Treg-speciﬁc CTLA-4 deﬁciency results in downregulation of where Tregs increase with disease stage suggesting induced CD80 and CD86 on DCs leading to loss of immunosuppression expansion of Tregs by tumor-related factors (74). Furthermore, (99). This happens in part through abrogated expression of the Treg numbers are also increased in the peripheral blood immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) of patients with breast, pancreatic (75), liver (70), gastric, by the DCs (100). When it comes to cancer, IDO is expressed and esophageal cancer (71) in comparison with blood from also within solid tumors from both tumor and stromal cells, healthy individuals. where it under normal conditions restrains an inﬂammatory Various studies have tried to identify the role of Tregs in reaction against cancer cells by degradation of tryptophan and immune evasion, and as it has become clear that the eﬀect recruitment of Tregs (101, 102). Another commonly known of Tregs on tumor progression vary according to the tumor checkpoint molecule is PD-1. PD-1 is a receptor expressed on type, the prognostic signiﬁcance of Treg inﬁltration remains a activated T cells, B cells, and myeloid cells. One of the early matter of debate. An overview of the clinical signiﬁcance in proofs of PD-1 being involved in maintenance of self-tolerance a range of cancers is provided in Table 1. In connection to came in 1999, where a knock-out mouse model showed that a the role of Tregs in evading immune recognition, a common defect in the PD-1 gene speciﬁcally predisposes to development presumption is that high numbers of Tregs within lymphoid of lupus-like autoimmune disease suggesting that PD-1 serves inﬁltrates can be predictive of relapse and dead. However, the as a negative regulator of immune responses (103). The same prognostic value of Tregs is somehow controversial as in some was seen in humans, where a study by Freeman et al. revealed cancers Tregs inﬁltration may exert a beneﬁcial role or can that engagement of PD-1 by its ligand PD-L1 led to inhibition of have both a negative and positive eﬀect on disease progression T cell receptor-mediated lymphocyte proliferation and cytokine and survival. The negative eﬀect on survival is observed in secretion (104). Furthermore, blockade of PD-1 seems to enhance pancreatic (87), liver (90), gastric, and esophageal cancer (74). recruitment of Teﬀ cells in intrasplenic tumors and prevent metastatic spread of several diﬀerent cancers (105). The crucial It is though more likely to observe opposing roles of Tregs in terms of survival in a wide range of cancer types such as role of CTLA-4 and PD-1 in regulation of a tolerogenic immune response opens up for a blockage of both checkpoint molecules cases of ovarian carcinoma (69, 76), colorectal cancer (85, 86), that may have great therapeutic potential in terms of activating melanoma (88), breast cancer (77–84), head and neck squamous an immune response against the cancer cells. Whereas, both cell carcinoma (91, 92), and lymphoma (93–96), where a high CTLA-4 and PD-1 function as negative regulators, GITR function frequency of Tregs improve disease-speciﬁc survival in some as a co-stimulatory receptor, leading to activation, proliferation patients and in others favors immune escape and tumor growth. and cytokine production in both Teﬀ and Treg cell populations Furthermore, in some patients there is no correlation between (106–108). As mentioned, GITR is expressed in high levels by Treg inﬁltration and disease progression at all (89). The reason for this discrepancy in the prognostic value of Treg inﬁltration Tregs, and has been shown to be increased in several cancer forms including breast cancer (42, 109, 110). Engagement of might be related to the diﬀerent nature of the cancers and the eﬀect of inﬂammation on tumor growth, but could also GITR on Treg cells has been shown to inhibit their suppressive function, and rendering Teﬀ unresponsive to Treg-mediated be dependent on the presence of diﬀerent Treg subsets in the suppression (106, 107). However, it has also been shown that diﬀerent malignancies. Frontiers in Immunology | www.frontiersin.org 6 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer Frontiers in Immunology | www.frontiersin.org 7 May 2019 | Volume 10 | Article 911 TABLE 1 | Examples of clinical signiﬁcance of Tregs in the tumor microenvironment. References Cancer Presence Treg deﬁnition Effect on clinical outcome Comment of Tregs Good/bad How + + + Curiel et al. (69) Ovarian carcinoma High CD4 CD25 FoxP3 Bad Reduced survival Treg cells suppress tumor-speciﬁc T cell immunity and contribute to growth of human tumors in vivo Milne et al. (76) Ovarian carcinoma High FoxP3 Good Increased disease-speciﬁc survival Tregs is associated with survival only in high-grade serous tumors from optimally debulked patients a + hi Gobert et al. (77) Breast cancer High CD4 CD25 Bad Higher risk of relapse and death Tregs are selectively recruited within lymphoid inﬁltrates and activated lo + CD127 FoxP3 by mature dendritic cells through tumor-associated antigens a + Demir et al. (78) Breast cancer High FoxP3 Bad Shorter overall survival The density of Treg inﬁltration before chemotherapy is a strong predictor for survival a + Sun et al. (79) Breast cancer High FoxP3 Bad Shorter disease-free survival Signiﬁcant correlation between expression of PD-1 in tumor-associated immune cells and FoxP3 cells − + + + West et al. (80) ER breast cancer High FoxP3 Good Prolonged recurrence-free survival FoxP3 Tregs are positively correlated with CD8 cytotoxic T cells and anti-tumor immunity + + Bates et al. (81) ER breast cancer High FoxP3 Bad Shorter relapse-free and overall High Treg numbers associated with high-grade tumors and lymph node survival involvement ER breast cancer - No impact + + + Liu et al. (82) ER breast cancer High FoxP3 Bad Poor survival High FoxP3 cell numbers are associated with young age, high grade, − + ER breast cancer Good Improved survival ER negativity, concurrent CD8 T cell inﬁltration, and HER2 positive ER subtypes + + + + Lee et al. (83) Triple-negative breast cancer High CD4 CD25 FoxP3 Good Improved survival High inﬁltration of FoxP3 Tregs is an independent prognostic factor for overall survival and progression free survival Liu et al. (84) Triple-negative breast cancer High FoxP3 Good Better overall and disease-free Elevated expression of Treg and immune-related genes is associated survival with more favorable outcome Frey et al. (85) Colorectal cancer High FoxP3 Good Improve disease-speciﬁc survival High frequency of tumor-inﬁltrating Tregs is associated with early T stage, tumor location, and increased 5-year survival rate + + + Chang et al. (86) Colorectal cancer High CD4 CD25 FoxP3 Bad Favor tumor growth CCL5/CCR5 signaling recruits Tregs to tumors and enhance their ability to kill antitumor CD8 T cells leading to immune escape + hi Kono et al. (74) Gastric and esophageal cancer High CD4 CD25 Bad Poor survival rate After curative resections of gastric cancers, the proportion of Tregs is signiﬁcantly reduced. In cases with recurrent tumors, levels increase again + + + Hiraoka et al. (87) Pancreatic ductal High CD4 CD25 FoxP3 Bad Poor prognosis The prevalence of Tregs increase signiﬁcantly during the progression of adenocarcinoma premalignant lesions + + + Miracco et al. (88) Primary cutaneous melanoma High CD4 CD25 FoxP3 Bad Predictive of recurrence The percentage of Tregs, both among tumor cells, inside tumor parenchyma and at periphery, is signiﬁcantly higher in cases that recurred Ladányi et al. (89) Primary cutaneous melanoma High FoxP3 - No prognostic impact The degree of Treg inﬁltration do not correlate with tumor thickness, metastasis, or survival. + + + Kobayashi et al. (90) Hepatocellular carcinoma High CD4 CD25 FoxP3 Bad Lower survival The prevalence of Tregs increase in a stepwise manner during the progression of hepatocarcinogenesis + + + + Badoual et al. (91) Head and neck squamous cell High CD4 FoxP3 Good Favorable Regulatory CD4 FoxP3 T cells are positively correlated with carcinoma locoregional control (Continued) Jørgensen et al. Tregs in Pregnancy and Cancer GITR induces IL-10 production, that if blocked leads to further GITR-mediated proliferation (108), leaving the exact role of GITR controversial. As shown in a study, the function of GITR on Treg cells is most likely context-dependent and rely on the model used to study its function, as well as the immunological milieu (111). Nevertheless, GITR is, like CTLA-4 and PD-1, an attractive target for immunotherapy, and GITR triggering using agonist antibodies and Fc-GITRL abrogates Treg-mediated suppression (106). Whereas, the function of tTregs is mainly cell-cell contact- dependent, the secretion of soluble factors, such as cytokines by iTregs and other Treg subtypes is essential for their hi function (Figure 2). IL-10 is a cytokine produced by CD44 Tregs and plays a central role both in parasitic infections (112), intestinal inﬂammation (113), and cancer (114) again emphasizing the involvement of similar mechanisms in diﬀerent pathophysiological conditions. In addition to IL-10, TGF-β is also produced by peripheral Tregs. Both IL-10 and TGF-β have pleiotrophic functions and have been implicated in both cancer progression as well as clearance [reviewed by (115)]. The eﬀect of IL-10 and TGF-β therefore most likely depends on the speciﬁc cancer type, and therapy targeting these cytokines should be done with careful considerations. Considering that Treg cells hi are deﬁned as CD25 , the high aﬃnity IL-2Rα chain, IL-2 is another cytokine central to both thymic and peripheral Treg development, function and homeostasis (116, 117). In contrast, the IL-7 receptor α chain, CD127, is low or absent in human Tregs, indicating that IL-7 is not required for Treg function, although a study in mice has suggested that IL-7 might be involved in early Treg development and in development of + lo CD4 FoxP3 Tregs (116, 117). Another increasingly acknowledged mechanism involved in development of cancer is regulation of the expression of HLA molecules in the tumor microenvironment. Increasing evidence suggest that expression of the classical and non- classical HLA class Ia (HLA-A, HLA-B, HLA-C) and class Ib (HLA-E, HLA-F, HLA-G) molecules inﬂuence immune regulation in a coordinated action with Tregs. This inﬂuence of HLA molecules is seen in multiple physiological and pathophysiological processes as the antigen-presenting capability of HLA molecules play a crucial role in infectious diseases, graft rejection, autoimmunity, reproduction, and cancer. Deregulation of the HLA class I molecules on the cancer cells leads to evasion of the host immune system (118). In a recent study on the prognostic value of tumor-stroma ratio combined with the immune status of the tumor, Vangangelt et al. showed that breast cancer patients with a stroma-low tumor and expression of classical HLA class I molecules have a better prognosis compared to patients with a stroma-high tumor and downregulation of HLA class I (119). Furthermore, when expression of HLA class Ia molecules are concomitantly lost, high expression of HLA-G is associated with a worse relapse-free period in breast cancer (120) and is suggested to facilitate invasion and increase the metastatic capacity of invasive ductal breast carcinoma (121– 123). In gastric cancer, HLA-G expression signiﬁcantly correlates with the presence of Tregs and is predictive of poorer survival (124). Expression of HLA-G and the presence of FoxP3 Frontiers in Immunology | www.frontiersin.org 8 May 2019 | Volume 10 | Article 911 TABLE 1 | Continued References Cancer Presence Treg deﬁnition Effect on clinical outcome Comment of Tregs Good/bad How + inter/hi hi Drennan et al. (92) Head and neck squamous cell High CD4 CD25 Bad Favor tumor progression Elevated frequency and suppressive activity of CD25 Tregs is lo/− carcinoma CD127 associated with advanced tumor stage and metastasis to lymph nodes + + Tzankov et al. (93) Lymphomas High FoxP3 Good Improved survival Increased number of FoxP3 cells positively inﬂuence survival in follicular lymphoma, germinal center-like diffuse large B cell lymphoma, and Hodgkin’s lymphoma Carreras et al. (94) Follicular lymphoma High FoxP3 Good Improved overall survival Patients with low Treg numbers presented more frequently with refractory disease Alvaro et al. (95) Hodgkin’s lymphoma Low FoxP3 Bad Unfavorable Low inﬁltration of Tregs in conjunction with cytotoxic lymphocytes is predictive of unfavorable outcome Schreck et al. (96) Hodgkin’s lymphoma High FoxP3 Bad/– Shorter disease-free survival A high ratio of Treg over Th2 cells is associated with shortened disease-free survival. Tregs have no prognostic impact alone Cohort of patients with advanced/invasive breast cancer irrespective of molecular subtype. Jørgensen et al. Tregs in Pregnancy and Cancer tumor-inﬁltrating lymphocytes is also believed to contribute antigens. Since tumor cells originate from normal cells and to the suppression of eﬀective T cell immune responses in develop within the context of self-tissue, most cancer antigens melanoma (68, 125). We have recently shown an association are self-antigens, and the immune mechanisms that prevent between high HLA-G expression and a high frequency of FoxP3 immune recognition of the tumor cells might function in similar tumor-inﬁltrating lymphocytes in malignant melanoma patients ways as those that prevent autoimmune attack of normal tissue (126). Furthermore, in an in vitro study we have demonstrated (133, 134). This is contrary to pregnancy, where both foreign that the HLA-G choriocarcinoma cell line JEG-3 originating and self-antigens are present from the semi-allogenic fetus and from placenta upregulates Tregs, and that the level of pro- immune suppression is necessary in order to avoid fetal rejection. inﬂammatory cytokines is modulated through HLA-G (127). However, it may be emphasized that cancer cells might eventually A subset of HLA-G-expressing T cells have also been shown to also, due to high mutational rate, express antigens foreign to the play a role in promoting a tolerogenic tumor microenvironment. body that can be recognized by Teﬀ cells. lo + A recent study found a population of CD4 HLA-G T cells A previous study by Wang et al. characterized tumor-speciﬁc associated with development of castration-resistant prostate CD4 T cells derived from a melanoma patient and were cancer in prostate cancer patients after treatment with androgen the ﬁrst to isolate antigen-speciﬁc Tregs, and further showed lo + deprivation therapy. Expansion of the CD4 HLA-G cells that cell-cell contact was required for T cell-mediated immune resulted in impaired immune surveillance and a tumor suppression in agreement with previous studies (135). The group microenvironment that were permissive of tumor growth (128). identiﬁed Tregs speciﬁc for LAGE1 and afterwards the ARCT- + + In pregnancy, CD4 HLA-G T cells have been reported and may 1 peptide (136). Tregs speciﬁc for a broad range of tumor be reduced in pre-eclampsia, although knowledge of a possible antigens including melanoma tissue diﬀerentiation antigens role of this subset is currently very limited (129). and cancer-testis antigen, have been identiﬁed in patients with We are currently investigating how expression of HLA class metastatic melanoma (137), and following studies performed Ia and Ib expression modulate the immune response in breast in colorectal cancer have also revealed tumor antigen-speciﬁc cancer with emphasis on Tregs and Natural Killer (NK) cells. Tregs (138). In colorectal cancer patients undergoing resection, By studying molecular and genetic changes of the immune a high level of FoxP3 Tregs speciﬁc for tumor antigens drives cells in contact with tumor cells we aim to identify molecular immunosuppression and correlates with tumor recurrence and markers associated with the regulatory function of the immune relapse (139). Studies in diabetic mice have revealed a superior cells and clinical outcome. Identiﬁcation of regulatory immune immunosuppressive activity for antigen-speciﬁc Tregs compared cell gene signatures in tumors can be important and relevant to non-speciﬁc Tregs (140, 141). Furthermore, Tregs responding when assessing the clinical course of the disease and prognosis. to self-antigens have also been shown to suppress anti-tumor A recent study focusing on immunogenic gene signatures in immune responses (142, 143). Indications are that Tregs are likely triple-negative breast cancer found a high expression of tumor- to play an important role in cancer immunology and elaborating inﬁltrating lymphocyte gene signatures in the tumor compared on the speciﬁcity of Tregs involved in antitumor responses could to normal tissues and that elevated levels of Treg gene sets be beneﬁcial from a therapeutic perspective. were consistently associated with better overall survival and disease free survival (84). This conﬁrms the controversy about the Immunotherapeutic Intervention in Cancer prognostic signiﬁcance of Tregs in the tumor microenvironment Given the role of Tregs in immune evasion and tumor and emphasizes the importance of research that can elaborate progression, several studies have already suggested that on the role of Tregs in a speciﬁc cancer setting and for the they are promising as therapeutic targets (31). Initially, individual patient. studies focused almost exclusively on the cancer cells as Substantial redundancy may exist in the mechanisms essential targets for therapeutic interventions. However, cancer cells for establishment and maintenance of immune tolerance (46). frequently acquire therapeutic resistance because of inherent Hence more research is necessary to identify mechanisms genetic instability. Hence, working toward manipulation, that could constitute the best targets for immunotherapeutic propagation, and therapeutic application of Tregs will provide treatment strategies. new and improved treatment options. The prognostic eﬀect of Tregs in diﬀerent cancer types is important to take into Antigen-Speciﬁc Tregs consideration when selecting a treatment strategy, and even With the aim to elucidate the role of Tregs in cancer though Tregs appear as an obvious target for anti-tumor development, several studies have found that the Treg response treatment, manipulation of Treg mechanisms is not that simple is an early event preceding the activation of Teﬀ cells (130, and more selective approaches for therapeutic strategies are 131). It was seen many years ago in mice, that a regulatory needed. This involves targeting of speciﬁc Treg subsets and immune response are present early followed by a decrease in the inhibition or activation of Tregs depending on the type of cellular reactivity against the tumor cells and a progressive loss cancer (30). Furthermore, the composition of other immune of immune recognition correlated with progression of tumor cells in the tumor microenvironment must also be taken growth (132). A mechanism by which Tregs are stimulated by the into account when assessing whether a patient will beneﬁt presence of the tumor is via recognition of antigens. from immunotherapy. Recently an immune biomarker task Tumors are believed to present tumor-speciﬁc antigen in the force elicited by the Society for Immunotherapy of Cancer form of neo-epitopes, sometimes known as tumor-associated (SITC) sought to make recommendations of immune-related Frontiers in Immunology | www.frontiersin.org 9 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer biomarkers that can predict the outcome of immunotherapy IDO (158). Hence, clinical trials have been initiated to evaluate in cancer patients (144). They focus on biomarkers in the the eﬃciency of IDO inhibitors and IDO-based vaccinations. A tumor microenvironment, gene expression at the tumor site, combination of pembrolizumab and the selective IDO inhibitor tumor antigens, mutational load, peripheral biomarkers, and Epacadostat initially showed promising results increasing the host-related genetic biomarkers. Overall, this suggest that a anti-tumor activity in patients with advanced solid tumors in combination of personalized diagnostics is necessary in order a phase I/II study (NCT02178722) (161). Unfortunately, no to assess immunocompentence of the individual. In terms of beneﬁt in survival was observed with the combined treatment this, an analysis of immune gene signatures should be feasible to compared to pembrolizumab alone in the following phase III determine the potential for immunotherapy. Liu et al. performed clinical trial (NCT02752074) (162). A clinical phase I study have an extensive analysis on immunogenic signatures in triple- shown that a vaccine with an epitope derived from IDO is well- negative breast cancer on two large-scale breast cancer genomic tolerated in patients with metastatic non-small cell lung cancer datasets. They demonstrated that this type of breast cancer has (NCT01219348) (163). Currently, a clinical phase 2 study is a strong tumor immunogenicity, which suggested that these testing a combination therapy of the PD1 antibody Nivolumab patients could beneﬁt from immunotherapy (84). and a vaccine consisting of PD-L1 and IDO (NCT03047928). Even though treatment by activation of the immune system A third way to enhance anti-tumor eﬀects is to deplete Tregs have proved to be successful it is not without side eﬀects. One of in the tumor microenvironment. Mouse studies have proven the the biggest challenges of targeting Tregs and blocking immune eﬀectiveness of eliminating Tregs by administration of IFN-γ checkpoints is the development of severe system immune-related and the use of IL-2 antibodies in combination with stimulation side eﬀects. Releasing the brake on the immune system can of eﬀector immune cells (140, 164). An ongoing clinical trial lead to a systemic immune activation and might cause extensive is investigating a combination of pembrolizumab and low- autoimmune reactions (31). dose IL-2 in patients with advanced melanoma or renal cell One branch of immunotherapy evolves around the idea cancer (NCT03111901). Furthermore, a phase I/II study have + + of activating the immune system targeting the regulatory shown that CD4 CD25 Treg depletion improves the graft- mechanisms that suppress an immune response against the vs.-tumor therapeutic eﬀect of donor lymphocyte infusion in cancer. Especially, cancer therapy by inhibition of negative patients suﬀering from hematopoietic malignancies and relapse immune regulation has proved very successful within recent after standard allogeneic hematopoietic stem cell transplantation years in the form of immune checkpoint inhibitors and are (NCT00987987) (165). currently used in cancer immunotherapy. Discovery of the Another branch of immunotherapy focuses on targeting two checkpoint molecules CTLA-4 and PD-1 that function as tumor antigens. Recognizing an increased activity for Tregs brakes on the immune system has led to a new approach for that are antigen-speciﬁc gave the idea that Tregs could also be treating cancer patients. Ipilimumab and tremelimumab are two exploited to target cancer cells. Expression of chimeric antigen well-characterized anti-CTLA-4 antibodies, the ﬁrst approved receptor (CAR) T cells to engineer T cells with antigen-speciﬁcity for treatment of malignant melanoma, colorectal cancer, and toward cancer cells have already oﬀered a promising strategy to renal cell carcinoma and the second being tested in clinical target diseases with extensive immune activation. This directs the trials on colorectal cancer and lung cancer patients (145–151). attention to a similar approach for Tregs with the possibility that Pembrolizumab is an anti-PD-1 drug approved for treatment of CAR Tregs could be used in Treg-mediated therapy reducing a multiple cancers including cervical cancer and melanoma (152– generalized immunosuppression (35). In terms of this, studies + + 155). Nivolumab is another anti-PD1 drug that in combination have shown that it is possible to isolate CD4 CD25 cells with with ipilimumab is used as ﬁrst-line treatment of melanoma immunosuppressive function from peripheral blood and expand being more eﬀective than either agent alone (156). Furthermore, them in vitro without loss of function, which represent a major nivolumab is shown to have a higher eﬃcacy as compared advance toward the therapeutic use of these cells in T cell- to chemotherapy in patients with melanoma, who progressed mediated diseases (166). So far, engineered Tregs have been after CTLA-4 treatment (157). These immunotherapies have shown to target the central nervous system reducing symptoms of emphasized how manipulation of immune regulation is essential multiple sclerosis by suppression of inﬂammation and in colitis for eradicating tumors. patients CAR T cells could hinder development of colorectal Another strategy of breaking the tolerance to tumor tissue cancer (167, 168). This indicate that the use of engineered Tregs is to inhibit the IDO pathway. Studies show that elimination is preferred in cancers with prominent inﬂammation and where of IDO-positive immunosuppressive cells change the regulatory immune suppression will have a beneﬁcial role in preventing microenvironment (158). Furthermore, it was found that 1- tumor progression. Moreover, a new study suggest a promising methyl-tryptophan isomers capable of blocking IDO activity is role for CAR T cells in delivery of checkpoint inhibitors. Mouse eﬀective in reversing the suppression of T cells promoted by CAR T cells was modiﬁed to secrete PD-1 blocking single-chain DCs (159). Combined with other immune activating drugs, IDO variable fragments and was shown to enhance the anti-tumor might also enhance the eﬃcacy of immunotherapy by preventing function in mouse models of hematologic and solid tumor (169). counter-regulation in response to immune activation (160). Hence, the targeted delivery of immune checkpoint inhibitors Combining induction of IDO-speciﬁc immune responses with or expression of other immunomodulatory molecules could anti-cancer immune therapy has the synergistic potential to both prevent systemic blockade, eventually improving treatment and eliminate cancer cells and immune suppressive cells expressing minimizing adverse side eﬀects. Frontiers in Immunology | www.frontiersin.org 10 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer THE ROLE OF TREGS IN REPRODUCTIVE (183). Roughly speaking, there are two compartments in the placenta in which maternal immune cells interact with the fetal BIOLOGY cells; the intervillous space and the decidua. The interactions between the fetal trophoblast cells and the maternal T cells will With the inheritance of half of the genes from the father, the fetus is considered to be semi-allogenic in an immunological sense. be diﬀerent at the two places. The intervillous space is the space This results in the immunological paradox in which the maternal between the anchoring villi, ﬂooded with maternal blood that allows exchange of nutrients. The syncytiotrophoblast cells here immune system has to be able to tolerate the presence of the foreign paternally derived antigens for a successful pregnancy lack the expression of all MHC/HLA molecules and should, in theory, not be able to interact with the maternal T cells to take place. Initially, a shift from a Th1 pro-inﬂammatory response toward an anti-inﬂammatory Th2 response has been (184). It has been suggested that the main role of the T cells located here is to protect mother and fetus against infectious the central paradigm to explain the generation of fetal tolerance (170). However, during normal pregnancy the decidua contains a pathogens (185). However, it should be noted that maternal + + antigen presenting cells (APCs) are still able to induce an adaptive decreased CD4 /CD8 ratio compared to the peripheral blood, and decreased numbers of CCR6 Th1, Th2, and Th17 cells, immune response by presenting paternal antigens despite the − + hi +/hi lack of MHC/HLA on the syncytiotrophoblast cells (186). In while CCR6 Th1 cells and CD4 CD25 FoxP3 Tregs are increased (171, 172). This reﬂects a much more complex scenario, contrast, invading extravillous trophoblasts (EVTs) present in the decidua express a unique combination of HLA-C and the non- and are now explained as a balance between Th1, Th2, Th17, and classical HLA-E, -F, and -G molecules, enabling them to elicit regulatory responses involving both innate and adaptive immune cells (173, 174). Moreover, recently it has been proposed that the immunosuppression and induce tolerance. The expression of a polymorphic paternally inherited HLA-C molecule on EVT has immune system plays diﬀerent roles in the diﬀerent phases of pregnancy; an inﬂammatory response seems necessary for the the potential to induce alloreactivity toward the fetal-derived cells. However, HLA-C is only expressed at a level of ∼10% of implantation of the blastocyst, while there is an establishment of a tolerogenic milieu for maintenance of the pregnancy, and HLA-A and -B, and HLA-C interacts both with T cells and NK cells through KIRs (7, 184). In addition to the local immune yet another shift toward inﬂammation at parturition (174, 175). To constrain inﬂammation and avoid fetal rejection, several changes happening in the placenta during pregnancy, peripheral tolerogenesis is also observed (187). It is not yet fully understood mechanisms have developed in which increasing focus has been giving to the role and function of the anti-inﬂammatory whether the peripheral changes reﬂects the local changes or if there is a separate systemic response to pregnancy, e.g., through properties of the regulatory Tregs (10, 173, 174, 176), which is described in the next section. interaction with shed trophoblast debris or exosomes. Although maternal Teﬀ cells are fully capable of recognizing Many studies have shown the importance of Tregs for pregnancy (10, 173, 174, 176). Tregs and FoxP3 mRNA have paternal antigens and become activated, this does not lead to rejection of the fetus (177, 178). Tafuri et al. were also able to been found in the endometrium throughout the menstrual cycle, increasing in the follicular/estrus phase and thereby show that paternally derived tumor cells were able to persist during pregnancy independent of antibody response, but was the receptive phase, suggesting that the uterus is preparing for pregnancy also involving immunomodulatory changes rejected after parturition (178). This indicates a pivotal role for establishment of a temporal state of tolerance against the (188, 189). Some studies might also indicate that the female immune system is primed for pregnancy through contact with paternal antigens during pregnancy, and thus an important role for Tregs (178, 179). Several mechanisms have been antigens and immunomodulatory molecules present in the seminal plasma during coitus (190). In mice, the CD4 and identiﬁed that protect the fetus from immune attack, including attenuated expression of polymorphic Major Histocompatibility CD8 Treg populations expand immediately after mating due Complex (MHC)/HLA proteins as well as expression of the to activation by paternally derived antigens present in the seminal ﬂuid (186). Pregnant women have a higher level of nearly monomorphic HLA class Ib molecules, release of anti- inﬂammatory hormones, cytokines, and immunomodulatory peripheral Tregs compared to non-pregnant women with Treg numbers peaking during ﬁrst and second trimester (191–194). molecules by the placenta, and suppression of allo-reactive responses (173). Fetal tolerance during pregnancy seems to be a In parallel, higher levels of Tregs can also be observed in certain cancer patients compared with healthy individuals as discussed balance between clonal exhaustion (i.e., deletion or inactivation) of allo-reactive T cells and immune regulation—a phenomenon brieﬂy previously. Moreover, it has been shown that women with infertility problems and women experiencing recurrent also seen in transplantation (180–182). During the formation of the maternal-fetal interphase fetal pregnancy loss (RPL) in ﬁrst trimester have reduced number of trophoblast cells will invade into the maternal decidua harboring Tregs and FoxP3 mRNA, indicating an early role for Tregs in maternal immune cells to form the placenta. In parallel, the the establishment of pregnancy (188, 195). The role of Tregs in tumor microenvironment can be seen as a pathological situation connection with the uterine (u)NK cells in the endometrium of with tumor cells with a distinct and possible non-self-phenotype infertile women has been thoroughly described in a recent review in close contact with immune cells (Figure 1). The placenta by Kofod et al. (196). Reduced numbers of Tregs, and increased is regarded as an immunological privileged site and is the number of CD8 T cells and Th17 cells, have also been associated source of many immunomodulatory molecules, hormones and with pregnancy complications such as pre-eclampsia (PE) and cytokines that contributes to establishment of fetal tolerance RPL (191, 192, 197). In mice, depletion of Tregs using anti-CD25 Frontiers in Immunology | www.frontiersin.org 11 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer monoclonal antibodies at the time of implantation resulted in in the human decidua (204, 205), Tregs seem to be recruited to poor implantation and fetal reabsorption in allogeneic, but not the uterus during estrus and in early pregnancy by chemokines in syngeneic pregnancies. In contrast, no eﬀect was observed such as CCL1, CCL4, CCL17, and CCL22 (171, 189, 206). on either pregnancy outcome, blood pressure or urinary protein In the pregnant mouse, the chemokine receptor CCR5 + + levels, when Tregs were depleted later in pregnancy (182). recognizing CCL4 is expressed by 70% of the CD4 CD25 This conﬁrms the proposed role for the Tregs in creating a Tregs, and interaction of CCR8 with CCL1 has been shown tolerogenic environment toward the paternal allo-antigens early to enhance the immunosuppressive function of the Tregs by in implantation and pregnancy. It has been suggested that both inducing FoxP3 expression and IL-10, TGF-β and Granzyme B thymic and induced peripheral Tregs play important roles in production (189, 207). pregnancy. Mice studies have shown that pre-existing thymic The fetal trophoblast cells also express and release a number memory/activated Tregs speciﬁc for self-antigens are present very of immunomodulatory molecules that contribute to the Treg early in pregnancy and thus play a role in implantation, whereas balance. Importantly, as seen in cancer and discussed above, depletion of peripheral Tregs leads to increased abortion later in the attenuated expression of polymorphic HLA molecules in hi pregnancy (198). In human ﬁrst trimester decidua, FoxP3 Tregs addition to the expression of the non-classical HLA class Ib, + + + with a similar phenotype (CD45RO HLA-DR CTLA-4 ) have which show very limited polymorphism, are believed to protect been identiﬁed (171). Analysis of Treg cells from term placenta the fetal trophoblast cells from a direct cytotoxic response by tissue also showed that these cells expressed GITR and had higher maternal Teﬀ and NK cells (7, 208–210). Moreover, interactions expression of CD25, CTLA-4, and CD69 in comparison to their with HLA-G have been shown to induce the development of peripheral counterparts, indicating an activated phenotype (194). immunosuppressive CD4 T cells and suppress APCs (211, Lastly, recent studies have shown that pregnancy also leads to 212). A special CD8αα Treg cell that speciﬁcally identiﬁes the generation of both eﬀector memory and central memory Qa-1a (equivalent to the human MHC class Ib molecule HLA- + + + CD4 and CD8 T cells that persist after pregnancy (199). The E), has been found to control activated CD4 T cells in development of memory Tregs after pregnancy and their possible mice (213). Furthermore, CD8αα cells have been shown to role for subsequent pregnancies remains to be elucidated. inﬁltrate the ovaries during ovulation. Although the origin and Despite these observations, the exact role of the Tregs are still characterization of the nature of the CD8αα cell was unclear, poorly understood. Also, the activation and generation of Tregs the CD8αα cells seemed to originate from the thymus and are dependent on recognition of antigen. Although mice studies responded to the thymus-expressed chemokine (TECK), which is have shown that allo-reactive T cells are clonally deleted and important for T cell development. Importantly, it was found that inactivated in a paternal antigen-speciﬁc manner, and like-wise, depletion of the CD8αα cells resulted in impaired fertility of the that Tregs recognizing paternal antigens are generated during female mice, suggesting a role in the establishment of pregnancy pregnancy, the exact nature and origin of the antigen responsible (214). The role of CD8 Tregs in pregnancy is unclear, however, for generation of pregnancy-speciﬁc Tregs in natural settings it would be interesting to study if any similar cell populations are are sparse (180, 182). More studies are needed to understand, important for pregnancy in humans. whether the role of the Tregs is speciﬁcally to limit harmful pro- Negative regulators such as PD-L1 (215), the TNF family inﬂammatory/Th1 and allo-reactive immune responses toward members FasL (CD95L or Apoptosis Antigen (APO)-1L) and the fetus, or whether the generation and function of the Tregs tumor necrosis factor-related apoptosis inducing ligand (TRAIL; are to limit general inﬂammatory responses in an environment CD235/APO-2L) (216–218) and IDO (219, 220) are also of tissue repair owed to the growing placenta (176). expressed by the trophoblast cells. These molecules, as described in previous sections, contribute to T cell homeostasis by inducing apoptosis in allo-reactive Teﬀ cells. Moreover, the trophoblast Mechanisms of Treg-Mediated cells also secrete IL-10 and TGF-β that contribute to Treg Immunosuppression in Pregnancy recruitment and diﬀerentiation (221, 222), of which IL-10 also The mechanisms of fetal tolerance in pregnancy are many has been shown to upregulate HLA-G, thus further contributing and cannot exclusively be attributed to the generation of to the Treg balance (223). As mentioned earlier, IL-10 and TGF- fetal-speciﬁc Tregs. Tolerance include a balance between β play an equally important role during cancer development. clonal deletion and/or inactivation of allo-reactive eﬀector However, in a cancer setting their pleiotrophic function imply cells and immune suppression mediated by regulatory subsets a more unclear eﬀect on the Treg balance depending on comprising both innate cells, such as tolerance-inducing DCs, cancer type. alternatively activated macrophages (M2) and the cytokine- The function of Tregs during pregnancy mirror those bright − producing CD56 CD16 decidual (d)NK cells, and adaptive occurring in the tumor microenvironment, in which Tregs + + cells, including CD4 and CD8 Tregs as well as regulatory B regulate other immune cells present in the maternal-fetal cells. All working together in an impressive network that secures interphase (Figures 1, 3). Tregs limit the eﬀect of allogen-speciﬁc a successful pregnancy (200–202). Teﬀ cells by the expression of CD25, CTLA-4, and the PD- Cells of the endometrium and placenta release L1 pathway and the secretion of IL-10 and TGF-β that induce numerous chemokines that play a role in orchestration of apoptosis and suppress cytotoxicity in recipient cells (171, 173, immunomodulatory cells (203). In contrast to dNK cells, which 176, 197). PD-L1 expression by Treg cells has been found + + − can be generated from CD34 hematopoietic precursors present to inhibit proliferation of CD4 CD25 T cells and suppress Frontiers in Immunology | www.frontiersin.org 12 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer + + expression of the pro-inﬂammatory cytokines IFN-γ and TNF- Tregs show an activated/memory phenotype (CD25 CD45RO ) α (224). PD-1 expression on T cells seem to be increased in as the classical Treg cells, but lack the expression of FoxP3 + + healthy pregnancy compared to non-pregnant women (225), (129). The CD4 HLA-G T cells are found at increased levels while reduced levels of PD-1 and PD-L1 have been suggested in peripheral blood in pregnant women compared with non- to promote Th17 proliferation, thus causing the Treg/Th17 pregnant women. Additionally, one study reported that the + + imbalance observed in PE (226). Consistent with this, mice placenta was enriched in CD4 HLA-G T cells compared studies have shown that blocking of PD-L1 results in lower to the peripheral compartment, and cases of PE have been + + numbers of Tregs and increased Teﬀ and Th17 populations, associated with reduced levels of the CD4 HLA-G T cell as well as increased fetal resorption and reduced litter size subpopulation in both the decidua and in peripheral blood, (227, 228). Moreover, engagement with PD-L1 and secretion indicating an important role for pregnancy (129). As mentioned of TGF-β promote the development of Tregs by increasing earlier, HLA-G-expressing T cells are also observed in the tumor FoxP3 expression, and reducing Teﬀ cell development (227). The microenvironment promoting a tolerogenic immune milieu, but immunosuppressive function of the PD1 pathway seems to work as with other immunological mechanisms having the same eﬀect by similar mechanisms in cancer and pregnancy, though with during pregnancy and cancer development, a favorable eﬀect is opposite eﬀect in terms of prognosis. Whereas, inhibition of the actually opposite in the two settings. Immune suppression by pathway is desirable for activating the immune response against HLA-G is crucial in terms of a healthy pregnancy, but unwanted cancer cells, activation and high PD-L1 expression is important in a cancer setting where it promotes tumor growth. in terms of promoting a healthy pregnancy. Taken together, it has become increasingly clear that Tregs The DCs are central for activation and diﬀerentiation of T cells are an important player in the complex network of immune by presenting antigen and providing co-stimulatory signaling. cells that secure a healthy pregnancy. Regulatory T cells are Formation of the placenta in early pregnancy is associated with central regulators at the maternal-fetal interphase, as well as in increased number of tolerogenic immature (i)DCs. These cells induction of peripheral tolerance during pregnancy. However, have been shown to produce increased levels of IL-10 and induce it is also evident that the Tregs cannot stand alone. The Treg formation during pregnancy (229–231). Further, Tregs Treg cells regulate and are regulated by a variety of cells and have been shown to induce the formation of anti-inﬂammatory immune modulatory molecules. Their exact role and the precise alternatively activated macrophages (M2), partly by IL-10 (232). mechanism by which they exert their immune regulation needs Moreover, Tregs secrete heme oxygenase-1 (HO-1) that keep to be further elucidated. DCs in an immature state in which they secrete higher amounts of IL-10 that further induce the formation of Tregs (233). In Immunotherapeutic Intervention in turn, these cells secrete IDO and TGF-β and engage with the CTLA-4 receptor on Tregs that together impairs allogen-speciﬁc Pregnancy Complications T cell activity and induce Treg formation, further aﬀecting the Clinical treatments based upon immunomodulating Treg Tregs/Teﬀ balance (234, 235). function in cases of infertility, pregnancy loss and pregnancy Uterine and decidual NK cells play important regulatory complications have not yet been implemented in routine settings. functions for the vascularization and formation of the placenta Regarding the use of Treg measurements as a diagnostic or in early pregnancy (236, 237). Like Tregs, a balance between prognostic marker, Winger and Reed have reported an interesting dim bright cytotoxic CD56 and regulatory CD56 NK cells seems but small study of 54 pregnant women with a history of infertility important for a successful pregnancy. Pregnancy complications and/or pregnancy loss (195). In a new pregnancy, 23 of the such as RPL and PE have also been linked to a reduced women experienced another pregnancy loss in the ﬁrst trimester, bright dim CD56 /CD56 NK cell ratio (238, 239). Tregs might also be and 31 women were still pregnant after 12 weeks of gestation. The + + + important in regulation of the dNK cell phenotype. It has been percentage of CD4 CD25 FoxP3 Tregs in peripheral blood shown that Tregs reduce cytotoxicity of NK cells in an TGF- was signiﬁcantly higher in the still pregnant >12 gestational β-dependent fashion and inhibit the release of IL-15 from DCs week compared with the pregnancy loss group at mean day 49.2 that are important for the generation of dNK cells (240, 241). ± 36.1 of the pregnancy. Based on the results from this pilot Likewise, TGF-β secreted from decidual stroma cells has been study the authors propose that measurements of Tregs may serve dim shown to change the peripheral CD56 toward a decidual- as a biomarker for the assessment of risk of pregnancy loss in bright like CD56 NK cell phenotype (242). It is likely that TGF-β newly pregnant women. Clearly, larger studies are needed to secreted from Tregs will have a similar eﬀect on the NK cell validate this. phenotype. On the contrary, NK cells are also able to contribute In a rat model of pregnancy loss induced by the administration to the Treg homeostasis by reducing Th17 cell responses through of lipopolysaccharide (LPS) resulting in maternal inﬂammation + + the production of IFN-γ and inducing CD25 FoxP3 Treg Renaud et al. showed that pregnancy loss could be prevented development (235, 243). by immunomodulation (244). This was either accomplished + +/hi + Apart from the classical CD4 CD25 FoxP3 T cells by administration of IL-10 or by blockade of TNF-α by described above, other types of Tregs have also been associated a TNF-α inhibitor (Etanercept). As discussed previously, with pregnancy. As brieﬂy addressed in previous sections recent studies especially in mice have shown the importance of the studies have identiﬁed an HLA-G-expressing CD4 T cell presence of Tregs for a successful pregnancy. In one study by population with immunosuppressive functions. The HLA-G Heitmann et al. a targeted depletion of Tregs was performed Frontiers in Immunology | www.frontiersin.org 13 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer using a transgenic mouse model (245). It was observed that distant ﬁelds like pregnancy and cancer have close connections embryo implantation in syngenic matings was defective after and could be highly beneﬁcial (246). This would involve a better Treg depletion. However, it was possible to restore embryo mapping of cytokine networks and e.g., interactions with HLA implantation by the transfer of Tregs into the mating mice. It class Ib molecules in both situations. can be speculated that administration or induction of pregnancy- Investigating the similarities in immunity through the related Tregs resembling engineered T cells used in cancer diﬀerent trimesters in pregnancy and in advanced malignancies treatment could rescue some unsuccessful pregnancies caused has the potential to advance the knowledge of mechanisms by abnormal Tregs function either by aberrant number of involved in Treg function and eventually help to overcome cells or a functional defect. There might also be therapeutic the burden of long-term antigen exposure and immunologic potential in blockage or the administration of speciﬁc cytokines exhaustion. Treatment strategies can be aimed at aspects such or HLA class Ib molecules locally in the female reproductive as invasion, angiogenesis, immune privilege, and malignant tract. In theory, such immunomodulation might be able to proliferation (5). We can take advantage of the knowledge from aﬀect numbers or functionality of regulatory T cell subsets the two diﬀerent ﬁelds of cancer and pregnancy complications beneﬁcial for a successful pregnancy. However, this therapeutic and potentially use it to facilitate the search for novel treatment area clearly needs more studies primarily to clarify the basic strategies in either of them. mechanisms upon which new therapeutic strategies may be Modiﬁcation of the presence of Tregs and the function of these based on. cells have been studied more extensively in relation to cancer then A reason as to why treatment based on immune modulation in the case of pregnancy complications, and treatment strategies is not extensively studied in terms of pregnancy complications targeting immunosuppressive pathways are already established compared to the ﬁeld of cancer immunotherapy, might be that for some cancers. However, more discoveries on Treg regulation the focus on the cause of pregnancy complications such as is essential for the exploitation of these cells both in the ﬁeld PE has been directed toward several diﬀerent factors besides of cancer and reproductive immunology in order to improve immune regulation. immunotherapy and to help prevent pregnancy complications. Similar for both ﬁelds, future research in interactions of Tregs with other cells, molecules responsible for recruitment of Tregs CONCLUSIONS AND PERSPECTIVES into the maternal-fetal interface and tumor site, and intracellular pathways of regulatory signaling in Treg cells, will be highly Many similarities exist in the regulatory immune landscape of valuable. Especially knowledge about the interactions of Tregs the tumor microenvironment and at the feto-maternal interface with other immune cells is needed to provide safe treatment and during pregnancy (Figure 1). While trophoblast cells possess to reduce immune-related side eﬀects (246). both maternal and paternal antigens, cancer is also a kind of a chimera consisting of cells presenting both self and tumor- associated antigens. Furthermore, it seems that the role of AUTHOR CONTRIBUTIONS Tregs in pregnancy and cancer, modulating the host response NJ, GP, and TH participated in the design and draft of the directed toward foreign antigens in the placenta and the manuscript. NJ is the main author of sections dealing with tumor, respectively, may not be very diﬀerent. Keeping this in Tregs in cancer, while GP drafted sections regarding Tregs mind, the immunosuppressive role of Tregs in pregnancy is in reproductive immunology. TH was responsible for overall a physiological process, while the inhibitory role of Tregs in supervision and did the ﬁnal proofreading of the draft. All cancer is pathophysiological, which nevertheless also makes the authors have read and accepted the ﬁnal version of the elaboration of immune modulating capacity in both cases even manuscript. The ﬁgures and the table included in the article more appealing. The apparent role of Tregs in early tolerance are made by the authors (Figure 1: TH and GP, Figures 2, 3: induction is another issue also important in both cancer and GP, Table 1: NJ), and the ﬁgures and the table have not been pregnancy. The early Treg response to embryo implantation is published before. similar to those in a cancer setting with Tregs being activated within the ﬁrst days of implantation and tumor emergence, respectively (5, 198). Most essential in reproduction and cancer FUNDING immunology is the similar mechanisms of escape from host immunosurveillance mediated by Tregs in combination with Support for this work was generously provided by The Region Zealand Health Sciences Research Foundation and Zealand other immune cells and immune factors. Therefore, investigating mechanisms engaging Tregs and their regulation in apparently University Hospital. REFERENCES 2. Waldmann H, Graca L, Cobbold S, Adams E, Tone M, Tone Y. Regulatory T cells and organ transplantation. Semin Immunol. (2004) 16:119–26. 1. Sakaguchi S. Naturally arising Foxp3-expressing CD25+ doi: 10.1016/j.smim.2003.12.007 CD4+ regulatory T cells in immunological tolerance to self 3. Wahl SM, Vázquez N, Chen W. Regulatory T cells and transcription factors: and non-self. Nat Immunol. (2005) 6:345–52. doi: 10.1038/n gatekeepers in allergic inﬂammation. Curr Opin Immunol. (2004) 16:768–74. i1178 doi: 10.1016/j.coi.2004.09.006 Frontiers in Immunology | www.frontiersin.org 14 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer 4. Munn DH, Mellor AL. The tumor-draining lymph node as xenogeneic response. Xenotransplantation. (2010) 17:121–30. an immune-privileged site. Immunol Rev. (2006) 213:146–58. doi: 10.1111/j.1399-3089.2010.00571.x doi: 10.1111/j.1600-065X.2006.00444.x 26. Liu W, Putnam AL, Xu-yu Z, Szot GL, Lee MR, Zhu S, et al. 5. Holtan SG, Creedon DJ, Haluska P, Markovic SN. Cancer and pregnancy: CD127 expression inversely correlates with FoxP3 and suppressive parallels in growth, invasion, and immune modulation and implications function of human CD4+ T reg cells. J Exp Med. (2006) 203:1701–11. for cancer therapeutic agents. Mayo Clin Proc. (2009) 84:985–1000. doi: 10.1084/jem.20060772 doi: 10.1016/S0025-6196(11)60669-1 27. Klein S, Kretz CC, Krammer PH, Kuhn A. CD127 low/and FoxP3 6. Hviid TVF. HLA-G in human reproduction: aspects of genetics, function expression levels characterize diﬀerent regulatory T-cell populations and pregnancy complications. Hum Reprod Update. (2006) 12:209–232. in human peripheral blood. J Invest Dermatol. (2010) 130:492–9. doi: 10.1093/humupd/dmi048 doi: 10.1038/jid.2009.313 7. Persson G, Melsted WN, Nilsson LL, Hviid TVF. HLA class Ib in 28. Chien C-H, Chiang BL. Regulatory T cells induced by B cells: a pregnancy and pregnancy-related disorders. Immunogenetics. (2017) 69:581– novel subpopulation of regulatory T cells. J Biomed Sci. (2017) 24:86. 95. doi: 10.1007/s00251-017-0988-4 doi: 10.1186/s12929-017-0391-3 8. Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell 29. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Res. (2017) 27:109–118. doi: 10.1038/cr.2016.151 Regulatory T cell lineage speciﬁcation by the forkhead transcription factor 9. Andersen MH. Immune regulation by self-recognition: novel possibilities Foxp3. Immunity. (2005) 22:329–41. doi: 10.1016/j.immuni.2005.01.016 for anticancer immunotherapy. J Natl Cancer Inst. (2015) 107:djv154. 30. Tanchot C, Terme M, Pere H, Tran T, Benhamouda N, Strioga M, doi: 10.1093/jnci/djv154 et al. Tumor-inﬁltrating regulatory T cells: phenotype, role, mechanism 10. Guerin LR, Prins JR, Robertson SA. Regulatory T-cells and immune tolerance of expansion in situ and clinical signiﬁcance. Cancer Microenviron. (2013) in pregnancy: a new target for infertility treatment? Hum Reprod Update. 6:147–57. doi: 10.1007/s12307-012-0122-y (2009) 15:517–35. doi: 10.1093/humupd/dmp004 31. Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment 11. Yu Y, Ma X, Gong R, Zhu J, Wei L, Yao J. Recent advances in CD8+regulatory and cancer progression: role and therapeutic targeting. Vaccines. (2016) 4:28. T cell research. Oncol Lett. (2018) 15:8187–94. doi: 10.3892/ol.2018.8378 doi: 10.3390/vaccines4030028 12. Zhang S, Wu M, Wang F. Immune regulation by CD8+ Treg cells: novel 32. Weiner HL. Induction and mechanism of action of transforming growth possibilities for anticancer immunotherapy. Cell Mol Immunol. (2018) factor-beta-secreting Th3 regulatory cells. Immunol Rev. (2001) 182:207–14. 15:805–7. doi: 10.1038/cmi.2018.170 doi: 10.1034/j.1600-065X.2001.1820117.x 13. Seddiki N, Santner-Nanan B, Tangye SG, Alexander SI, Solomon M, Lee S, 33. Zeng H, Zhang R, Jin B, Chen L. Type 1 regulatory T cells: a new mechanism et al. Persistence of naive CD45RA+ regulatoryTcells in adult life. Blood. of peripheral immune tolerance. Cell Mol Immunol. (2015) 12:566–71. (2006) 107:2830–2838. doi: 10.1182/blood-2005-06-2403.Supported doi: 10.1038/cmi.2015.44 14. Gershon RK, Cohen P, Hencin R, Liebhaber SA. Suppressor T cells. J 34. Jonuleit H, Schmitt E. The regulatory T cell family: distinct Immunol. (1972) 108:586–90. subsets and their interrelations. J Immunol. (2003) 171:6323–7. 15. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self- doi: 10.4049/jimmunol.171.12.6323 tolerance maintained by activated T cells expressing IL-2 receptor alpha- 35. Hoeppli RE, MacDonald KG, Levings MK, Cook L. How antigen speciﬁcity chains (CD25). Breakdown of a single mechanism of self-tolerance causes directs regulatory T-cell function: self, foreign and engineered speciﬁcity. various autoimmune diseases. J Immunol. (1995) 155:1151–64. HLA. (2016) 88:3–13. doi: 10.1111/tan.12822 16. Thornton AM, Shevach EM. CD4 + CD25 + immunoregulatory T Cells 36. Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey- Suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 Bucktrout S, et al. Neuropilin-1 distinguishes natural and inducible production. J Exp Med. (1998) 188:287–96. doi: 10.1084/jem.188.2.287 regulatory T cells among regulatory T cell subsets in vivo. J Exp Med. (2012) 17. Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, 209:1713–22. doi: 10.1084/jem.20120822 et al. Immunologic self-tolerance maintained by CD25+CD4+naturally 37. Shevach EM, Thornton AM. tTregs, pTregs, and iTregs: similarities and anergic and suppressive T cells: Induction of autoimmune disease by diﬀerences. Immunol Rev. (2014) 259:88–102. doi: 10.1111/imr.12160 breaking their anergic/suppressive state. Int Immunol. (1998) 10:1969–80. 38. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, doi: 10.1093/intimm/10.12.1969 Belkaid Y, et al. Expression of Helios, an Ikaros transcription factor 18. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. family member, diﬀerentiates thymic-derived from peripherally Identiﬁcation and functional characterization of human Cd4 + Cd25 + T induced Foxp3 + T regulatory cells. J Immunol. (2010) 184:3433–1. cells with regulatory properties isolated from peripheral blood. J Exp Med. doi: 10.4049/jimmunol.0904028 (2001) 193:1285–94. doi: 10.1084/jem.193.11.1285 39. Lin X, Chen M, Liu Y, Guo Z, He X, Brand D, et al. Advances in 19. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, David A, et al. distinguishing natural from induced Foxp3+ regulatory T cells. Int J. Human CD4+CD25+ cells : a naturally occurring population of regulatory (2013) 6:116–23. Retrieved from: http://www.ijcep.com/. T cells. Blood. (2013) 98:2736–44. doi: 10.1182/blood.V98.9.2736 40. Dunussi-Joannopoulos K, LaBranche TP, Ryan MS, Medley QG, Keegan 20. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo SP, Collins M, et al. Enhanced GITR/GITRL interactions augment IL-27 isolation and characterization of Cd4 + Cd25 + T cells with regulatory expression and induce IL-10-producing Tr-1 like cells. Eur J Immunol. (2012) properties from human blood. J Exp Med. (2001) 193:1303–10. 42:1393–404. doi: 10.1002/eji.201142162 doi: 10.1084/jem.193.11.1303 41. Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y, Owen DL, et al. 21. Baecher-Allan C, Brown JA, Freeman GJ, Haﬂer DA. CD4+CD25high Tumor necrosis factor receptor superfamily costimulation couples T cell regulatory cells in human peripheral blood. J Immunol. (2001) 167:1245–53. receptor signal strength to thymic regulatory T cell diﬀerentiation. Nat doi: 10.4049/jimmunol.167.3.1245 Immunol. (2014) 15:473–81. doi: 10.1038/nature08728.An 22. Hori S. Control of regulatory T cell development by the transcription factor 42. Ronchetti S, Ricci E, Petrillo MG, Cari L, Migliorati G, Nocentini G, et al. Foxp3. Science. (2003) 299:1057–61. doi: 10.1126/science.1079490 Glucocorticoid-induced tumour necrosis factor receptor-related protein: 23. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for a key marker of functional regulatory T cells. J Immunol Res. (2015) Scurﬁn in CD4+CD25+T regulatory cells. J Immunol. (2003) 198:993–8. 2015:171520. doi: 10.1155/2015/171520 doi: 10.1038/ni909 43. Andrews LP, Marciscano AE, Drake CG, Vignali DAA. LAG3 (CD223) 24. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development as a cancer immunotherapy target. Immunol Rev. (2017) 276:80–96. and function of CD4+CD25+ regulatory T cells. Nat Immunol. (2003) doi: 10.1111/imr.12519 4:330–6. doi: 10.1038/ni904 44. Antonioli L, Pacher P, Vizi ES, Haskó G. CD39 and CD73 in 25. Sun L, Yi S, O’Connell PJ. Foxp3 regulates human natural immunity and inﬂammation. Trends Mol Med. (2013) 19:355–67. CD4+CD25+ regulatory T-cell-mediated suppression of doi: 10.1016/j.molmed.2013.03.005 Frontiers in Immunology | www.frontiersin.org 15 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer 45. Mandapathil M, Szczepanski MJ, Szajnik M, Ren J, Jackson EK, Johnson 64. Pankratz S, Ruck T, Meuth SG, Wiendl H. CD4+HLA-G+ regulatory T JT, et al. Adenosine and prostaglandin e2 cooperate in the suppression of cells: molecular signature and pathophysiological relevance. Hum Immunol. immune responses mediated by adaptive regulatory T cells. J Biol Chem. (2016) 77:727–33. doi: 10.1016/j.humimm.2016.01.016 (2010) 285:27571–80. doi: 10.1074/jbc.M110.127100 65. Fridman WH, Pagès F, Sauts-Fridman C, Galon J. The immune contexture 46. Campbell DJ, Koch MA. Phenotypical and functional specialization in human tumours: impact on clinical outcome. Nat Rev Cancer. (2012) of FOXP3+ regulatory T cells. Nat Rev Immunol. (2011) 11:119–30. 12:298–306. doi: 10.1038/nrc3245 doi: 10.1038/nri2916 66. Whiteside T. The role of regulatory T cells in cancer immunology. 47. Suto A, Nakajima H, Ikeda K, Kubo S, Nakayama T, Taniguchi M, ImmunoTargets Ther. (2015) 4:159–71. doi: 10.2147/ITT.S55415 et al. CD4+CD25+T-cell development is regulated by at least 2 distinct 67. Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-inﬁltrating mechanisms. Blood. (2002) 99:555–60. doi: 10.1182/blood.V99.2.555 FoxP3+regulatory T cells in cancers: a systematic review and meta-analysis. 48. Pacholczyk R, Kraj P, Ignatowicz L. Peptide speciﬁcity of thymic Sci Rep. (2015) 5:15179. doi: 10.1038/srep15179 selection of CD4+CD25+ T cells. J Immunol. (2002) 168:613–20. 68. Jacobs JFM, Nierkens S, Figdor CG, de Vries IJM, Adema GJ. Regulatory doi: 10.4049/jimmunol.168.2.613 T cells in melanoma: The ﬁnal hurdle towards eﬀective immunotherapy? 49. Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, Lancet Oncol. (2012) 13:e32–42. doi: 10.1016/S1470-2045(11)70155-3 et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an 69. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. agonist self-peptide. Nat Immunol. (2001) 2:301–6. doi: 10.1038/86302 Speciﬁc recruitment of regulatory T cells in ovarian carcinoma fosters 50. Thornton AM, Shevach EM. Suppressor eﬀector function of CD4+CD25+ immune privilege and predicts reduced survival. Nat Med. (2004) 10:942–9. Immunoregulatory T cells is antigen nonspeciﬁc. J Immunol. (2000) doi: 10.1038/nm1093 164:183–90. doi: 10.4049/jimmunol.164.1.183 70. Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, 51. Kosten IJ, Rustemeyer T. Generation, subsets and functions of inducible Korangy F. Increased Populations of Regulatory T cells in peripheral blood regulatory T cells. Antiinﬂamm Antiallergy Agents Med Chem. (2015) of patients with hepatocellular carcinoma. Cancer Res. (2005) 65:2457–64. 13:139–53. doi: 10.2174/1871523013666141126100019 doi: 10.1158/0008-5472.CAN-04-3232 52. Passerini L, Di Nunzio S, Gregori S, Gambineri E, Cecconi M, Seidel MG, 71. Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H. Increased et al. Functional type 1 regulatory T cells develop regardless of FOXP3 populations of regulatory T cells in peripheral blood and tumor-inﬁltrating mutations in patients with IPEX syndrome. Eur J Immunol. (2011) 41:1120– lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res. 31. doi: 10.1002/eji.201040909 (2003) 9:4404–8. Retrieved from: http://clincancerres.aacrjournals.org. 53. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion 72. Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Endl E, et al. Reduced of peripheral CD4 CD25 naive T cells to CD4 CD25 regulatory T cells by frequencies and suppressive function of CD4+ CD25 hi regulatory T cells in TGF-induction of transcription factor Foxp3. J Exp Med J Exp Med. (2003) patients with chronic lymphocytic leukemia after therapy with ﬂudarabine. 198:1875–86. doi: 10.1084/jem.20030152 Blood. (2005) 106:2018–25. doi: 10.1182/blood-2005-02-0642.Supported 54. Bacchetta R, Sartirana C, Levings MK, Bordignon C, Narula S, 73. Bohling SD, Allison KH. Immunosuppressive regulatory T cells are Roncarolo MG. Growth and expansion of human T regulatory associated with aggressive breast cancer phenotypes: a potential therapeutic type 1 cells are independent from TCR activation but require target. Mod Pathol. (2008) 21:1527–32. doi: 10.1038/modpathol.2008.160 exogenous cytokines. Eur J Immunol. (2002) 32:2237–45. 74. Kono K, Kawaida H, Takahashi A, Sugai H, Mimura K, Miyagawa N, et al. doi: 10.1002/1521-4141(200208)32:8<2237::AID-IMMU2237>3.0.CO;2-2 CD4(+)CD25high regulatory T cells increase with tumor stage in patients 55. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, et al. with gastric and esophageal cancers. Cancer Immunol Immunother. (2006) A CD4+T-cell subset inhibits antigen-speciﬁc T-cell responses and prevents 55:1064–71. doi: 10.1007/s00262-005-0092-8 colitis. Nature. (1997) 389:737–42. doi: 10.1038/39614 75. Liyanage UK, Moore TT, Joo H-GH-G, Tanaka Y, Herrmann V, 56. Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt Doherty G, et al. Prevalence of regulatory T cells is increased in R, Roncarolo MG. IFN-a and IL-10 induce the diﬀerentiation of peripheral blood and tumor microenvironment of patients with human Type 1 T regulatory cells. J Immunol. (2001) 166:5530–9. pancreas or breast adenocarcinoma. J Immunol. (2002) 169:2756–61. doi: 10.4049/jimmunol.166.9.5530 doi: 10.4049/jimmunol.169.5.2756 57. Levings MK, Bacchetta R, Schulz U, Roncarolo MG. The role of IL-10 and 76. Milne K, Köbel M, Kalloger SE, Barnes RO, Gao D, Gilks CB, et al. Systematic TGF-beta in the diﬀerentiation and eﬀector function of T regulatory cells. analysis of immune inﬁltrates in high-grade serous ovarian cancer reveals Int Arch Allergy Immunol. (2002) 129:263–76. doi: 10.1159/000067596 CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS ONE. (2009) 58. Chen Y, Kuchroo V, Inobe J, Haﬂer D, Weiner H. Regulatory T cell clones 4:e6412. doi: 10.1371/journal.pone.0006412 induced by oral tolerance: suppression of autoimmune encephalomyelitis. 77. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon Science. (1994) 265:1237–40. doi: 10.1126/science.7520605 S, Arﬁ V, et al. Regulatory T cells recruited through CCL22/CCR4 are 59. Weiner HL. The mucosal milieu creates tolerogenic dendritic cells and TR1 selectively activated in lymphoid inﬁltrates surrounding primary breast and TH3 regulatory cells. Nat Immunol. (2001) 2:671–2. doi: 10.1038/90604 tumors and lead to an adverse clinical outcome. Cancer Res. (2009) 69:2000– 60. Fukaura H, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Haﬂer 9. doi: 10.1158/0008-5472.CAN-08-2360 DA. Induction of circulating myelin basic protein and proteolipid protein- 78. Demir L, Yigit S, Ellidokuz H, Erten C, Somali I, Kucukzeybek Y, et al. speciﬁc transforming growth factor-beta1-secreting Th3 T cells by oral Predictive and prognostic factors in locally advanced breast cancer: eﬀect administration of myelin in multiple sclerosis patients. J Clin Invest. (1996) of intratumoral FOXP3+ Tregs. Clin Exp Metastasis. (2013) 30:1047–62. 98:70–7. doi: 10.1172/JCI118779 doi: 10.1007/s10585-013-9602-9 61. Feger U, Tolosa E, Huang Y-H, Waschbisch A, Biedermann T, Melms A, 79. Sun S, Fei X, Mao Y, Wang X, Garﬁeld DH, Huang O, et al. PD- et al. HLA-G expression deﬁnes a novel regulatory T-cell subset present in 1+ immune cell inﬁltration inversely correlates with survival of operable human peripheral blood and sites of inﬂammation. Blood. (2007) 110:568– breast cancer patients. Cancer Immunol Immunother. (2014) 63:395–406. 77. doi: 10.1182/blood-2006-11-057125 doi: 10.1007/s00262-014-1519-x 62. Pankratz S, Bittner S, Herrmann AM, Schuhmann MK, Ruck T, Meuth 80. West NR, Kost SE, Martin SD, Milne K, Deleeuw RJ, Nelson BH, et al. SG, et al. Human CD4 + HLA-G + regulatory T cells are potent Tumour-inﬁltrating FOXP3 + lymphocytes are associated with cytotoxic suppressors of graft-versus-host disease in vivo. FASEB J. (2014) 28:3435–45. immune responses and good clinical outcome in oestrogen receptor-negative doi: 10.1096/fj.14-251074 breast cancer. Br J Cancer. (2013) 108:155–62. doi: 10.1038/bjc.2012.524 63. Huang YH, Zozulya AL, Weidenfeller C, Schwab N, Wiendl H. T cell 81. Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, et al. Quantiﬁcation suppression by naturally occurring HLA-G-expressing regulatory CD4 + of regulatory T cells enables the identiﬁcation of high-risk breast cancer T cells is IL-10-dependent and reversible. J Leukoc Biol. (2009) 86:273–81. patients and those at risk of late relapse. J Clin Oncol. (2006) 24:5373–80. doi: 10.1189/jlb.1008649 doi: 10.1200/JCO.2006.05.9584 Frontiers in Immunology | www.frontiersin.org 16 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer 82. Liu S, Foulkes WD, Leung S, Gao D, Lau S, Kos Z, et al. Prognostic ovarian carcinoma patients. Proc Natl Acad Sci USA. (2003) 100:4712–7. signiﬁcance of FOXP3+ tumor-inﬁltrating lymphocytes in breast doi: 10.1073/pnas.0830997100 cancer depends on estrogen receptor and human epidermal growth 99. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, factor receptor-2 expression status and concurrent cytotoxic T-cell Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T inﬁltration. Breast Cancer Res. (2014) 16:432. doi: 10.1186/s13058-01 cell function. Science. (2008) 322:271–5. doi: 10.1126/science.11 4-0432-8 60062 83. Lee S, Cho EY, Park YH, Ahn JS, Im YH. Prognostic impact of FOXP3 100. Onodera T, Jang MH, Guo Z, Yamasaki M, Hirata T, Bai Z, et al. Constitutive expression in triple-negative breast cancer. Acta Oncol. (2013) 52:73–81. expression of IDO by dendritic cells of mesenteric lymph nodes: functional doi: 10.3109/0284186X.2012.731520 involvement of the CTLA-4/B7 and CCL22/CCR4 interactions. J Immunol. 84. Liu Z, Li M, Jiang Z, Wang X. A comprehensive immunologic (2009) 183:5608–14. doi: 10.4049/jimmunol.0804116 portrait of triple-negative breast cancer. Transl Oncol. (2018) 11:311–29. 101. Godin-Ethier J, Hanaﬁ LA, Piccirillo CA, Lapointe R. Indoleamine doi: 10.1016/j.tranon.2018.01.011 2,3-dioxygenase expression in human cancers: clinical and 85. Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, et al. immunologic perspectives. Clin Cancer Res. (2011) 17:6985–91. High frequency of tumor-inﬁltrating FOXP3 + regulatory T cells predicts doi: 10.1158/1078-0432.CCR-11-1331 improved survival in mismatch repair-proﬁcient colorectal cancer patients. 102. Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: Int J Cancer. (2010) 2643:2635–43. doi: 10.1002/ijc.24989 beyond IDO and tryptophan depletion. Cancer Res. (2012) 72:5435–40. 86. Chang LY, Lin YC, Mahalingam J, Huang CT, Chen TW, Kang CW, et al. doi: 10.1158/0008-5472.CAN-12-0569 Tumor-derived chemokine CCL5 enhances TGF- -mediated killing of CD8+ 103. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of T cells in colon cancer by T-regulatory cells. Cancer Res. (2012) 72:1092–102. lupus-like autoimmune diseases by disruption of the PD-1 gene encoding doi: 10.1158/0008-5472.CAN-11-2493 an ITIM motif-carrying immunoreceptor. Immunity. (1999) 11:141–51. 87. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ doi: 10.1016/S1074-7613(00)80089-8 regulatory T cells increases during the progression of pancreatic ductal 104. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. adenocarcinoma and its premalignant lesions. Clin Cancer Res. (2006) Engagement of the Pd-1 immunoinhibitory receptor by a novel B7 family 12:5423–34. doi: 10.1158/1078-0432.CCR-06-0369 member leads to negative regulation of lymphocyte activation. J Exp Med. 88. Miracco C, Mourmouras V, Biagioli M, Rubegni P, Mannucci S, Monciatti (2000) 192:1027–34. doi: 10.1084/jem.192.7.1027 I, et al. Utility of tumour-inﬁltrating CD25+FOXP3+ regulatory T cell 105. Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread evaluation in predicting local recurrence in vertical growth phase cutaneous of poorly immunogenic tumor cells by enhanced recruitment of eﬀector T melanoma. Oncol Rep. (2007) 18:1115–22. doi: 10.3892/or.18.5.1115 cells. Int Immunol. (2005) 17:133–44. doi: 10.1093/intimm/dxh194 89. Ladányi A, Mohos A, Somlai B, Liszkay G, Gilde K, Fejos Z, et al. 106. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation FOXP3+cell density in primary tumor has no prognostic impact in patients of CD25+CD4+ regulatory T cells through GITR breaks immunological with cutaneous malignant melanoma. Pathol Oncol Res. (2010) 16:303–9. self-tolerance. Nat Immunol. (2002) 3:135–42. doi: 10.1038/ni759 doi: 10.1007/s12253-010-9254-x 107. Stephens GL, Collins M, Shevach EM, Carreno BM, McHugh RS, 90. Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge Young DA, et al. Engagement of Glucocorticoid-induced TNFR family- T, et al. FOXP3+ Regulatory T cells aﬀect the development and related receptor on eﬀector T cells by its ligand mediates resistance to progression of hepatocarcinogenesis. Clin Cancer Res. (2007) 13:902–11. suppression by CD4+CD25+ T cells. J Immunol. (2014) 173:5008–20. doi: 10.1158/1078-0432.CCR-06-2363 doi: 10.4049/jimmunol.173.8.5008 91. Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay NEH, et al. 108. Hashiguchi S, Nishioka T, Takahashi T, Kanamaru F, Youngnak P. Prognostic value of tumor-inﬁltrating CD4+ T-cell subpopulations T cells + regulatory CD4 + CD25 TNF receptor in both conventional in head and neck cancers. Clin Cancer Res. (2006) 12:465–72. and costimulation via Glucocorticoid-induced Sakaguchi, Isao doi: 10.1158/1078-0432.CCR-05-1886 Ishikawa and Miyuki Azuma. J Immunol Ref. (2004) 172:7306–7314. 92. Drennan S, Staﬀord ND, Greenman J, Green VL. Increased frequency and doi: 10.4049/jimmunol.172.12.7306 suppressive activity of CD127 low/- Tregs in the peripheral circulation of 109. Krausz LT, Fischer-Fodor E, Majorl ZZ, Fetica B. Gitr-expressing patients with head and neck squamous cell carcinoma are associated with regulatory T-cell subsets are increased in tumor-positive lymph advanced stage and nodal involvement. Immunology. (2013) 140:335–43. nodes from advanced breast cancer patients as compared to tumor- doi: 10.1111/imm.12144 negative lymph nodes. Int J Immunopathol Pharmacol. (2012) 25:59–66. 93. Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. doi: 10.1177/039463201202500108 Correlation of high numbers of intratumoral FOXP3+ regulatory T 110. Silva JS, Tiezzi DG, Benevides L, Andrade JM, Marana HRC, Cardoso CRB. cells with improved survival in germinal center-like diﬀuse large B- Enrichment of regulatory T cells in invasive breast tumor correlates with cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. the upregulation of IL-17A expression and invasiveness of the tumor. Eur Haematologica. (2008) 93:193–200. doi: 10.3324/haematol.11702 J Immunol. (2013) 43:1518–28. doi: 10.1002/eji.201242951 94. Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G, 111. Ephrem A, Epstein AL, Stephens GL, Thornton AM, Glass D, Shevach EM. et al. High numbers of tumor-inﬁltrating FOXP3-positive regulatory T cells Modulation of Treg cells/T eﬀector function by GITR signaling is context- are associated with improved overall survival in follicular lymphoma. Blood. dependent. Eur J Immunol. (2013) 43:2421–9. doi: 10.1002/eji.201343451 (2006) 108:2957–64. doi: 10.1182/blood-2006-04-018218 112. Belkaid Y, Piccirillo CA, Mendez S. CD4+ CD25+ regulatory T cells control 95. Álvaro T, Lejeune M, Salvadó MT, Bosch R, García JF, Jaén J, et al. Leishmania major persistence and immunity. Nature. (2002) 420:633–7. Outcome in Hodgkin’s lymphoma can be predicted from the presence of doi: 10.1038/nature01199.1 accompanying cytotoxic and regulatory T cells. Clin Cancer Res. (2005) 113. Asseman C, Mauze S, Leach MW, Coﬀman RL, Powrie F. An essential role 11:1467–73. doi: 10.1158/1078-0432.CCR-04-1869 for interleukin 10 in the function of regulatory T cells that inhibit intestinal 96. Schreck S, Friebel D, Buettner M, Distel L, Grabenbauer G, Young LS, inﬂammation. J Exp Med. (1999) 190:995–1004. doi: 10.1084/jem.190.7.995 et al. Prognostic impact of tumour-inﬁltrating Th2 and regulatory T 114. Loser K, Apelt J, Voskort M, Mohaupt M, Balkow S, Schwarz T, et al. IL- cells in classical Hodgkin lymphoma. Hematol Oncol. (2009) 27:31–9. 10 controls ultraviolet-induced carcinogenesis in mice. J Immunol. (2007) doi: 10.1002/hon.878 179:365–71. doi: 10.4049/jimmunol.179.1.365 97. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor 115. Landskron G, la Fuente MD, Thuwajit P, Thuwajit C, Hermoso MA. Chronic immunity by CTLA-4 blockade. Adv Sci. (2010) 271:1734–6. Inﬂammation and Cytokines in the Tumor Microenvironment. J Immunol doi: 10.1126/science.271.5256.1734 Res. (2014) 2014:149185. doi: 10.1155/2014/149185 98. Hodi FS, Mihm MC, Soiﬀer RJ, Haluska FG, Butler M, Seiden MV, 116. Surh CD, Bayer AL, de la Barrera A, Lee JY, Malek TR. A function for IL-7R et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 for CD4+CD25+Foxp3+ T regulatory cells. J Immunol. (2014) 181:225–34. antibody blockade in previously vaccinated metastatic melanoma and doi: 10.4049/jimmunol.181.1.225 Frontiers in Immunology | www.frontiersin.org 17 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer 117. Hoeppli RE, Wu D, Cook L, Levings MK. The environment of regulatory 136. Wang HY, Peng G, Guo Z, Shevach EM, Wang RF. Recognition of T cell biology: cytokines, metabolites, and the microbiome. Front Immunol. a New ARTC1 peptide ligand uniquely expressed in tumor cells by (2015) 6:61. doi: 10.3389/ﬁmmu.2015.00061 antigen-speciﬁc CD4+ regulatory T cells. J Immunol. (2005) 174:2661–70. 118. Carosella ED, Rouas-Freiss N, Le Roux DT, Moreau P, LeMaoult J. HLA-G. doi: 10.4049/jimmunol.174.5.2661 An Immune Checkpoint Molecule. Adv Immunol. 1st ed. Paris: Elsevier Inc. 137. Vence L, Palucka AK, Fay JW, Ito T, Liu Y-J, Banchereau J, et al. (2015) 127:33–144. doi: 10.1016/bs.ai.2015.04.001 Circulating tumor antigen-speciﬁc regulatory T cells in patients with 119. Vangangelt KMH, van Pelt GW, Engels CC, Putter H, Liefers GJ, Smit metastatic melanoma. Proc Natl Acad Sci USA. (2007) 104:20884–9. VTHBM, et al. Prognostic value of tumor–stroma ratio combined with the doi: 10.1073/pnas.0710557105 immune status of tumors in invasive breast carcinoma. Breast Cancer Res 138. Bonertz A, Weitz J, Pietsch DK, Rahbari NN, Schlude C, Ge Y, et al. Treat. (2017) 168:601–12. doi: 10.1007/s10549-017-4617-6 Antigen-speciﬁc Tregs control T cell responses against a limited repertoire of 120. de Kruijf EM, Sajet A, van Nes JGH, Natanov R, Putter H, Smit VTHBM, tumor antigens in patients with colorectal carcinoma. J Clin Investig. (2009) et al. HLA-E and HLA-G expression in classical HLA class I-negative tumors 119:3311–21. doi: 10.1172/JCI39608.tumor is of prognostic value for clinical outcome of early breast cancer patients. J 139. Betts G, Jones E, Junaid S, El-Shanawany T, Scurr M, Mizen P, et al. Immunol. (2010) 185:7452–59. doi: 10.4049/jimmunol.1002629 Suppression of tumour-speciﬁc CD4 + T cells by regulatory T cells 121. Ramos CS, Gonçalves AS, Marinho LC, Gomes Avelino MA, Saddi VA, Lopes is associated with progression of human colorectal cancer. Gut. (2012) AC, et al. Analysis of HLA-G gene polymorphism and protein expression 61:1163–71. doi: 10.1136/gutjnl-2011-300970 in invasive breast ductal carcinoma. Hum Immunol. (2014) 75:667–72. 140. Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, et al. Visualizing doi: 10.1016/j.humimm.2014.04.005 regulatory T cell control of autoimmune responses in nonobese diabetic 122. Ueshima C, Kataoka TR, Hirata M, Furuhata A, Suzuki E, Toi M, et al. mice. Nat Immunol. (2006) 7:83–92. doi: 10.1038/ni1289 The killer cell Ig-like receptor 2DL4 expression in human mast cells and 141. Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. CD25 + CD4 its potential role in breast cancer invasion. Cancer Immunol Res. (2015) + T cells, expanded with dendritic cells presenting a single autoantigenic 3:871–80. doi: 10.1158/2326-6066.CIR-14-0199 peptide, suppress autoimmune diabetes. J Exp Med. (2004) 199:1467–77. 123. da Silva GBRF, Silva TGA, Duarte RA, Neto NL, Carrara HHA, Donadi EA, doi: 10.1084/jem.20040180 et al. Expression of the classical and nonclassical HLA molecules in breast 142. Nishikawa H, Kato T, Tanida K, Hiasa A, Tawara I, Ikeda H, et al. CD4+ cancer. Int J Breast Cancer. (2013) 2013:250435. doi: 10.1155/2013/250435 CD25+ T cells responding to serologically deﬁned autoantigens suppress 124. Du L, Xiao X, Wang C, Zhang X, Zheng N, Wang L, et al. Human leukocyte antitumor immune responses. Proc Natl Acad Sci USA. (2003) 100:10902–6. antigen-G is closely associated with tumor immune escape in gastric cancer doi: 10.1073/pnas.1834479100 by increasing local regulatory T cells. Cancer Sci. (2011) 102:1272–80. 143. Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, et al. doi: 10.1111/j.1349-7006.2011.01951.x Aire-dependent thymic development of tumor-associated regulatory T cells. 125. Adrián Cabestré F, Moreau P, Riteau B, Ibrahim EC, Le Danﬀ Science. (2013) 339:1219–24. doi: 10.1126/science.1233913 C, Dausset J, et al. HLA-G expression in human melanoma cells: 144. Gnjatic S, Bronte V, Brunet LR, Butler MO, Disis ML, Galon J, et al. Protection from NK cytolysis. J Reprod Immunol. (1999) 43:183–93. Identifying baseline immune-related biomarkers to predict clinical doi: 10.1016/S0165-0378(99)00037-6 outcome of immunotherapy. J Immunother Cancer. (2017) 5:44. 126. Melsted WN, Johansen LL, Lock-Andersen J, Behrendt N, Eriksen JO, Bzorek doi: 10.1186/s40425-017-0243-4 M, et al. HLA class Ia and Ib molecules and FOXP3+ TILs in relation to the 145. Fellner C. Ipilimumab (yervoy) prolongs survival in advanced melanoma: prognosis of malignant melanoma patients. Clin Immunol. (2017) 183:191–7. serious side eﬀects and a hefty price tag may limit its use. P T. (2012) doi: 10.1016/j.clim.2017.09.004 37:503–30. Retrieved from: https://www.ptcommunity.com/. 127. Melsted WN, Matzen SH, Andersen MH, Hviid TVF. The choriocarcinoma 146. Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. cell line JEG-3 upregulates regulatory T cell phenotypes and modulates pro- Durable clinical beneﬁt with nivolumab plus ipilimumab in DNA mismatch inﬂammatory cytokines through HLA-G. Cell Immunol. (2017) 324:14–23. repair–deﬁcient/microsatellite instability–high metastatic colorectal cancer. doi: 10.1016/j.cellimm.2017.11.008 J Clin Oncol. (2018) 36:773–9. doi: 10.1200/JCO.2017.76.9901 128. Wang C, Chen J, Zhang Q, Li W, Zhang S, Xu Y, et al. Elimination of CD4 low 147. Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok HLA-G+ T cells overcomes castration- resistance in prostate cancer therapy. JD, Schmidt H, et al. Prolonged survival in stage III melanoma (2018) Cell Res. (2018) 28:1103–17. doi: 10.1038/s41422-018-0089-4 with ipilimumab adjuvant therapy. N Engl J Med. (2016) 375:1845–55. 129. Hsu P, Santner-Nanan B, Joung S, Peek MJ, Nanan R. Expansion of doi: 10.1056/NEJMoa1611299 CD4+HLA-G+T cell in human pregnancy is impaired in pre-eclampsia. Am 148. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. J Reprod Immunol. (2014) 71:217–28. doi: 10.1111/aji.12195 Improved survival with ipilimumab in patients with metastatic melanoma. N 130. Darrasse-Jèze G, Podsypanina K. How numbers, nature, and immune Engl J Med. (2010) 363:711–23. doi: 10.1056/NEJMoa1003466 status of Foxp3+regulatory T-cells shape the early immunological events in 149. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar tumor development. Front Immunol. (2013) 4:292. doi: 10.3389/ﬁmmu.2013. B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib 00292 in advanced renal-cell carcinoma. N Engl J Med. (2018) 378:1277–90. 131. Darrasse-Jèze G, Bergot A, Durgeau A, Billiard F, Salomon BL, Cohen JL, doi: 10.1056/NEJMoa1712126 et al. Tumor emergence is sensed by self-speciﬁc CD44hi memory Tregs that 150. Fumet J-D, Isambert N, Hervieu A, Zanetta S, Guion J-F, Hennequin A, create a dominant tolerogenic environment for tumors in mice. J Clin Invest. et al. Phase Ib/II trial evaluating the safety, tolerability and immunological (2009) 119:2648–62. doi: 10.1172/JCI36628 activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti- 132. Bhatnagar RM, Zabriskie JB, Rausen AR. Cellular immune responses to CTLA-4) combined with FOLFOX in patients with metastatic colorectal methylcholanthrene-induced ﬁbrosarcoma in BALB/c mice. J Exp Med. cancer. ESMO Open. (2018) 3:e000375. doi: 10.1136/esmoopen-2018-0 (1975) 142:839–55. doi: 10.1084/jem.142.4.839 00375 133. Savage PA, Leventhal DS, Malchow S. Shaping the repertoire of tumor- 151. Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta inﬁltrating eﬀector and regulatory T cells. Immunol Rev. (2014) 259:245–58. A, et al. Safety and antitumour activity of durvalumab plus tremelimumab doi: 10.1111/imr.12166 in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 134. Lu Y-C, Robbins PF. Cancer immunotherapy targeting neoantigens. Semin (2016) 17:299–308. doi: 10.1016/S1470-2045(15)00544-6 Immunol. (2016) 28:22–7. doi: 10.1016/j.smim.2015.11.002 152. Martínez P, del Campo JM. Pembrolizumab in recurrent advanced 135. Wang HY, Lee DA, Peng G, Guo Z, Li Y, Kiniwa Y, et al. cervical squamous carcinoma. Immunotherapy. (2017) 9:467–70. Tumor-speciﬁc human CD4+regulatory T cells and their ligands: doi: 10.2217/imt-2016-0119 implications for immunotherapy. Immunity. (2004) 20:107–18. 153. Frenel J-S, Le Tourneau C, O’Neil B, Ott PA, Piha-Paul SA, Gomez-Roca C, doi: 10.1016/S1074-7613(03)00359-5 et al. Safety and eﬃcacy of pembrolizumab in advanced, programmed death Frontiers in Immunology | www.frontiersin.org 18 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer ligand 1–positive cervical cancer: results from the phase Ib KEYNOTE-028 Immunol Today. (1993) 14:353–6. doi: 10.1016/0167-5699(93) trial. J Clin Oncol. (2017) 35:4035–41. doi: 10.1200/JCO.2017.74.5471 90235-D 154. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. 171. Mjösberg J, Berg G, Jenmalm MC, Ernerudh J. FOXP3+ regulatory Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. T cells and T Helper 1, T Helper 2, and T Helper 17 cells in (2015) 372:2521–32. doi: 10.1056/NEJMoa1503093 human early pregnancy Decidua1. Biol Reprod. (2010) 82:698–705. 155. Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, doi: 10.1095/biolreprod.109.081208 et al. Pembrolizumab versus ipilimumab for advanced melanoma: 172. Erkers T, Stikvoort A, Uhlin M. Lymphocytes in placental tissues: immune ﬁnal overall survival results of a multicentre, randomised, open- regulation and translational possibilities for immunotherapy. Stem Cells Int. label phase 3 study (KEYNOTE-006). Lancet. (2017) 390:1853–62. (2017) 2017:1–17. doi: 10.1155/2017/5738371 doi: 10.1016/S0140-6736(17)31601-X 173. Robertson SA, Care AS, Moldenhauer LM. Regulatory T cells in embryo 156. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, implantation and the immune response to pregnancy. J Clin Invest. (2018) et al. Combined nivolumab and ipilimumab or monotherapy in untreated 128:4224–35. doi: 10.1172/JCI122182 melanoma. N Engl J Med. (2015) 373:23–34. doi: 10.1056/NEJMoa1504030 174. Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T- 157. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. cell paradigm in pregnancy. Am J Reprod Immunol. (2010) 63:601–10. Nivolumab versus chemotherapy in patients with advanced melanoma who doi: 10.1111/j.1600-0897.2010.00852.x progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, 175. Chavan AR, Griﬃth OW, Wagner GP. The inﬂammation paradox in the controlled, open-label, phase 3 trial. Lancet Oncol. (2015) 16:375–84. evolution of mammalian pregnancy: turning a foe into a friend. Curr Opin doi: 10.1016/S1470-2045(15)70076-8 Genet Dev. (2017) 47:24–32. doi: 10.1016/j.gde.2017.08.004 158. Andersen MH. The speciﬁc targeting of immune regulation: T-cell responses 176. Powell RM. Novel T Cell Function and Speciﬁcity at the Human Maternal- against Indoleamine 2,3-dioxygenase. Cancer Immunol Immunother. (2012) Fetal Interface. (2018) Available online at: http://etheses.bham.ac.uk/8334/ 61:1289–97. doi: 10.1007/s00262-012-1234-4 (accessed September 4, 2018). 159. Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, et al. 177. Tilburgs T, Scherjon SA, van der Mast BJ, Haasnoot GW, Versteeg- Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers V.D.Voort-Maarschalk M, Roelen DL, et al. Fetal-maternal HLA-C of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res. mismatch is associated with decidual T cell activation and induction (2007) 67:792–801. doi: 10.1158/0008-5472.CAN-06-2925 of functional T regulatory cells. J Reprod Immunol. (2009) 82:147–56. 160. Munn DH. Indoleamine 2,3-dioxygenase, tumor-induced tolerance doi: 10.1016/j.jri.2009.05.003 and counter-regulation. Curr Opin Immunol. (2006) 18:220–5. 178. Tafuri A, Alferink J, Möller P, Hämmerling GJ, Arnold B. T cell awareness doi: 10.1016/j.coi.2006.01.002 of paternal alloantigens during pregnancy. Science. (1995) 270:630–3. 161. Mitchell TC, Hamid O, Smith DC, Bauer TM, Wasser JS, Olszanski doi: 10.1126/science.270.5236.630 AJ, et al. Epacadostat plus pembrolizumab in patients with advanced 179. Gleicher N, Kushnir VA, Barad DH. Redirecting reproductive immunology solid tumors: phase I results from a multicenter, open-label phase research toward pregnancy as a period of temporary immune tolerance. J I/II trial (ECHO-202/KEYNOTE-037). J Clin Oncol. (2018) 36:3223–30. Assist Reprod Genet. (2017) 34:425–30. doi: 10.1007/s10815-017-0874-x doi: 10.1200/JCO.2018.78.9602 180. Jiang SP, Vacchio MS. Multiple mechanisms of peripheral T cell tolerance to 162. Long GV, Dummer R, Hamid O, Gajewski T, Caglevic C, Dalle S, et al. the fetal “allograft”. J Immunol. (1998) 160:3086–90. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in 181. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat patients (pts) with unresectable or metastatic melanoma: results of the Rev Immunol. (2003) 3:223–32. doi: 10.1038/nri1029 phase 3 ECHO-301/KEYNOTE-252 study. J Clin Oncol. (2018) 36:108. 182. Shima T, Sasaki Y, Itoh M, Nakashima A, Ishii N, Sugamura K, et al. doi: 10.1200/JCO.2018.36.15_suppl.108 Regulatory T cells are necessary for implantation and maintenance of early 163. Iversen TZ, Engell-Noerregaard L, Ellebaek E, Andersen R, Larsen SK, pregnancy but not late pregnancy in allogeneic mice. J Reprod Immunol. Bjoern J, et al. Long-lasting disease stabilization in the absence of toxicity (2010) 85:121–9. doi: 10.1016/j.jri.2010.02.006 in metastatic lung cancer patients vaccinated with an epitope derived 183. Rusterholz C, Hahn S, Holzgreve W. Role of placentally produced from indoleamine 2,3 dioxygenase. Clin Cancer Res. (2014) 20:221–32. inﬂammatory and regulatory cytokines in pregnancy and the doi: 10.1158/1078-0432.CCR-13-1560 etiology of preeclampsia. Semin Immunopathol. (2007) 29:151–62. 164. Antony PA, Paulos CM, Ahmadzadeh M, Akpinarli A, Palmer DC, Sato doi: 10.1007/s00281-007-0071-6 N, et al. Interleukin-2-dependent mechanisms of tolerance and immunity 184. Apps R, Murphy SP, Fernando R, Gardner L, Ahad T, Moﬀett A. Human in vivo. J Immunol. (2006) 176:5255–66. doi: 10.4049/jimmunol.176.9.5255 leucocyte antigen (HLA) expression of primary trophoblast cells and 165. Maury S, Lemoine FM, Hicheri Y, Rosenzwajg M, Badoual C, Cherai placental cell lines, determined using single antigen beads to characterize M, et al. CD4+CD25+ regulatory T cell depletion improves the allotype speciﬁcities of anti-HLA antibodies. Immunology. (2009) 127:26–39. graft-versus-tumor eﬀect of donor lymphocytes after allogeneic doi: 10.1111/j.1365-2567.2008.03019.x hematopoietic stem cell transplantation. Sci Transl Med. (2010) 2:41ra52. 185. Solders M, Gorchs L, Erkers T, Lundell AC, Nava S, Gidlöf S, et al. doi: 10.1126/scitranslmed.3001302 MAIT cells accumulate in placental intervillous space and display a highly 166. Levings MK, Sangregorio R, Roncarolo M-G. Human CD25+CD4+ T cytotoxic phenotype upon bacterial stimulation. Sci Rep. (2017) 7:6123. regulatory cells suppress naive and memory T cell proliferation and can be doi: 10.1038/s41598-017-06430-6 expanded in vitro without loss of function. J Exp Med. (2001) 193:1295–302. 186. Moldenhauer LM, Diener KR, Thring DM, Brown MP, Hayball JD, doi: 10.1084/jem.193.11.1295 Robertson SA. Cross-presentation of male seminal ﬂuid antigens elicits T cell 167. Blat D, Zigmond E, Alteber Z, Waks T, Eshhar Z. Suppression of murine activation to initiate the female immune response to pregnancy. J Immunol. colitis and its associated cancer by carcinoembryonic antigen-speciﬁc (2009) 182:8080–93. doi: 10.4049/jimmunol.0804018 regulatory T cells. Mol Ther. (2014) 22:1018–28. doi: 10.1038/mt.2014.41 187. Jin LP, Chen QY, Zhang T, Guo PF, Li DJ. The CD4+CD25bright regulatory 168. Fransson M, Piras E, Burman J, Nilsson B, Essand M, Lu B, et al. T cells and CTLA-4 expression in peripheral and decidual lymphocytes are CAR/FoxP3-engineered T regulatory cells target the CNS and suppress down-regulated in human miscarriage. Clin Immunol. (2009) 133:402–10. EAE upon intranasal delivery. J Neuroinﬂammation. (2012) 9:576. doi: 10.1016/J.CLIM.2009.08.009 doi: 10.1186/1742-2094-9-112 188. Jasper MJ, Tremellen KP, Robertson SA. Primary unexplained infertility is 169. Raﬁq S, Yeku OO, Jackson HJ, Purdon TJ, van Leeuwen DG, Drakes associated with reduced expression of the T-regulatory cell transcription DJ, et al. Targeted delivery of a PD-1-blocking scFV by CAR-T cells factor Foxp3 in endometrial tissue. Mol Hum Reprod. (2006) 12:301–8. enhances anti-tumor eﬃcacy in vivo. Nat Biotechnol. (2018) 36:847–58. doi: 10.1093/molehr/gal032 doi: 10.1038/nbt.4195 189. Kallikourdis M, Betz AG. Periodic accumulation of regulatory T cells in the 170. Wegmann TG, Lin H, Mosmann TR. Bidirectional cytokine interactions in uterus: Preparation for the implantation of a semi-allogeneic fetus? PLoS the maternal-fetal relationshi : is successful pregnancy a Th 2 phenomenon? ONE. (2007) 2:e382. doi: 10.1371/journal.pone.0000382 Frontiers in Immunology | www.frontiersin.org 19 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer 190. Robertson SA, Guerin LR, Moldenhauer LM, Hayball JD. Activating fertilization and pregnancy outcome. Tissue Antigens. (2004) 64:66–9. T regulatory cells for tolerance in early pregnancy-the contribution of doi: 10.1111/j.1399-0039.2004.00239.x seminal ﬂuid. J Reprod Immunol. (2009) 83:109–16. doi: 10.1016/j.jri.2009. 209. Ishitani A, Sageshima N, Lee N, Dorofeeva N, Hatake K, Marquardt 08.003 H, et al. Protein expression and peptide binding suggest unique 191. Sasaki Y, Darmochwal-Kolarz D, Suzuki D, Sakai M, Ito M, Shima T, and interacting functional roles for HLA-E, F, and G in maternal- et al. Proportion of peripheral blood and decidual CD4(+) CD25(bright) placental immune recognition. J Immunol. (2003) 171:1376–84. regulatory T cells in pre-eclampsia. Clin Exp Immunol. (2007) 149:139–45. doi: 10.4049/jimmunol.171.3.1376 doi: 10.1111/j.1365-2249.2007.03397.x 210. Contini P, Ghio M, Poggi A, Filaci G, Indiveri F, Ferrone S, et al. Soluble 192. Santner-Nanan B, Peek MJ, Khanam R, Richarts L, Zhu E, Fazekas de St. HLA-A,-B,-C and -G molecules induce apoptosis in T and NK CD8+ cells Groth B, et al. Systemic increase in the ratio between Foxp3+ and IL-17- and inhibit cytotoxic T cell activity through CD8 ligation. Eur J Immunol. producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J (2003) 33:125–34. doi: 10.1002/immu.200390015 Immunol. (2009) 183:7023–30. doi: 10.1111/j.1096-3642.1945.tb00854.x 211. Horuzsko A, Lenfant F, Munn DH, Mellor AL. Maturation of antigen- 193. Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal presenting cells is compromised in HLA-G transgenic mice. Int Immunol. human pregnancy is associated with an elevation in the immune suppressive (2001) 13:385–94. doi: 10.1093/intimm/13.3.385 CD25 + CD4 + regulatory T-cell subset. Immunology. (2004) 112:38–43. 212. LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED. HLA- doi: 10.1111/j.1365-2567.2004.01869.x G1-expressing antigen-presenting cells induce immunosuppressive 194. Heikkinen J, Möttönen M, Alanen A, Lassila O. Phenotypic characterization CD4+ T cells. Proc Natl Acad Sci USA. (2004) 101:7064–9. of regulatory T cells in the human decidua. Clin Exp Immunol. (2004) doi: 10.1073/pnas.0401922101 136:373–8. doi: 10.1111/j.1365-2249.2004.02441.x 213. Tang X, Maricic I, Purohit N, Bakamjian B, Reed-Loisel LM, Beeston 195. Winger EE, Reed JL. Low Circulating CD4+ CD25+ Foxp3+ T T, et al. Regulation of immunity by a novel population of Qa-1- regulatory cell levels predict miscarriage risk in newly pregnant women restricted CD8 +TCR + T cells. J Immunol. (2006) 177:7645–55. with a history of failure. Am J Reprod Immunol. (2011) 66:320–8. doi: 10.4049/jimmunol.177.11.7645 doi: 10.1111/j.1600-0897.2011.00992.x 214. Zhou C, Wu J, Borillo J, Torres L, McMahon J, Lou YH. Potential roles 196. Kofod L, Lindhard A, Hviid TVF. Implications of uterine NK cells and of a special CD8 + cell population and CC chemokine thymus-expressed regulatory T cells in the endometrium of infertile women. Hum Immunol. chemokine in ovulation related inﬂammation. J Immunol. (2009) 182:596– (2018) 79:693–701. doi: 10.1016/j.humimm.2018.07.003 603. doi: 10.4049/jimmunol.182.1.596 197. Abdolmohammadi Vahid S, Ghaebi M, Ahmadi M, Nouri M, Danaei 215. Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman S, Aghebati-Maleki L, et al. Altered T-cell subpopulations in recurrent GJ, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during pregnancy loss patients with cellular immune abnormalities. J Cell Physiol. normal and autoimmune responses. Eur J Immunol. (2003) 33:2706–16. (2018) 234:4924–33. doi: 10.1002/jcp.27290 doi: 10.1002/eji.200324228 198. Chen T, Darrasse-Jeze G, Bergot AS, Courau T, Churlaud G, Valdivia K, et al. 216. Mor G, Gutierrez LS, Eliza M, Kahyaoglu F, Arici A. Fas-Fas Self-speciﬁc memory regulatory t cells protect embryos at implantation in ligand system-induced apoptosis in human placenta and gestational mice. J Immunol. (2013) 191:2273–81. doi: 10.4049/jimmunol.1202413 trophoblastic disease. Am J Reprod Immunol. (1998) 40:89–94. 199. Kieﬀer TEC, Faas MM, Scherjon SA, Prins JR. Pregnancy persistently doi: 10.1111/j.1600-0897.1998.tb00396.x aﬀects memory T cell populations. J Reprod Immunol. (2017) 119:1–8. 217. Stenqvist AC, Nagaeva O, Baranov V, Mincheva-Nilsson L. Exosomes doi: 10.1016/j.jri.2016.11.004 secreted by human placenta carry functional Fas Ligand and TRAIL 200. Liu S, Diao L, Huang C, Li Y, Zeng Y, Kwak-Kim JYH. The role of decidual molecules and convey apoptosis in activated immune cells, suggesting immune cells on human pregnancy. J Reprod Immunol. (2017) 124:44–53. exosome-mediated immune privilege of the fetus. J Immunol. (2013) doi: 10.1016/j.jri.2017.10.045 191:5515–23. doi: 10.4049/jimmunol.1301885 201. Munoz-Suano A, Hamilton AB, Betz AG. Gimme shelter: the 218. Vacchio MS, Hodes RJ. Fetal expression of Fas Ligand is necessary immune system during pregnancy. Immunol Rev. (2011) 241:20–38. and suﬃcient for induction of CD8 T cell tolerance to the fetal doi: 10.1111/j.1600-065X.2011.01002.x antigen H-Y during pregnancy. J Immunol. (2005) 174:4657–61. 202. Muzzio D, Zenclussen AC, Jensen F. The role of B cells in pregnancy: doi: 10.4049/jimmunol.174.8.4657 the good and the bad. Am J Reprod Immunol. (2013) 69:408–12. 219. Hönig A, Rieger L, Kapp M, Sütterlin M, Dietl J, Kämmerer U. Indoleamine doi: 10.1111/aji.12079 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast 203. Ramhorst R, Grasso E, Paparini D, Hauk V, Gallino L, Calo G, et al. Decoding supports role of the enzyme for materno-fetal tolerance. J Reprod Immunol. the chemokine network that links leukocytes with decidual cells and the (2004) 61:79–86. doi: 10.1016/J.JRI.2003.11.002 trophoblast during early implantation. Cell Adh Migr. (2016) 10:197–207. 220. Zong S, Li C, Luo C, Zhao X, Liu C, Wang K, et al. Dysregulated expression doi: 10.1080/19336918.2015.1135285 of IDO may cause unexplained recurrent spontaneous abortion through 204. Chiossone L, Vacca P, Orecchia P, Croxatto D, Damonte P, Astigiano suppression of trophoblast cell proliferation and migration. Sci Rep. (2016) S, et al. In vivo generation of decidual natural killer cells from 6:19916. doi: 10.1038/srep19916 resident hematopoietic progenitors. Haematologica. (2014) 99:448–57. 221. Ramhorst R, Fraccaroli L, Aldo P, Alvero AB, Cardenas I, Leirós CP, doi: 10.3324/haematol.2013.091421 et al. Modulation and recruitment of inducible regulatory T cells by 205. Vacca P, Vitale C, Montaldo E, Conte R, Cantoni C, Fulcheri E, et al. ﬁrst trimester trophoblast cells. Am J Reprod Immunol. (2012) 67:17–27. CD34 + hematopoietic precursors are present in human decidua and doi: 10.1111/j.1600-0897.2011.01056.x diﬀerentiate into natural killer cells upon interaction with stromal cells. 222. Roth I, Corry DB, Locksley RM, Abrams JS, Litton MJ, Fisher SJ. Human Proc Natl Acad Sci USA. (2010) 108:2402–7. doi: 10.1073/pnas.10162 placental cytotrophoblasts produce the immunosuppressive cytokine 57108 interleukin 10. J Exp Med. (1996) 184:539–48. doi: 10.1084/jem.184.2.539 206. Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia 223. Moreau P, Adrian-Cabestre F, Menier C, Guiard V, Gourand L, Dausset J, F, et al. Unique chemotactic response proﬁle and speciﬁc expression of et al. IL-10 selectively induces HLA-G expression in human trophoblasts and chemokine receptors Ccr4 and Ccr8 by Cd4 + Cd25 + regulatory T cells. monocytes. Int Immunol. (1999) 11:803–11. J Exp Med. (2001) 194:847–54. doi: 10.1084/jem.194.6.847 224. Habicht A, Dada S, Jurewicz M, Fife BT, Yagita H, Azuma M, et al. A link 207. Barsheshet Y, Wildbaum G, Levy E, Vitenshtein A, Akinseye C, Griggs J, between PDL1 and T regulatory cells in fetomaternal tolerance. J Immunol. et al. CCR8 + FOXp3 + T reg cells as master drivers of immune regulation. (2007) 179:5211–19. doi: 10.4049/jimmunol.179.8.5211 Proc Natl Acad Sci USA. (2017) 114:6086–91. doi: 10.1073/pnas.16212 225. Grozdics E, Berta L, Bajnok A, Veres G, Ilisz I, Klivényi P Jr, et al. B7 80114 costimulation and intracellular indoleamine-2, 3-dioxygenase (IDO) 208. Hviid TVF, Hylenius S, Lindhard A, Christiansen OB. Association expression in peripheral blood B7 costimulation and intracellular between human leukocyte antigen-G genotype and success of in vitro indoleamine-2, 3-dioxygenase (IDO) expression in peripheral Frontiers in Immunology | www.frontiersin.org 20 May 2019 | Volume 10 | Article 911 Jørgensen et al. Tregs in Pregnancy and Cancer blood of healthy pregnant and non-pregnant women 3-dioxygen. 238. Fukui A, Yokota M, Funamizu A, Nakamua R, Fukuhara R, Yamada K, BMC Pregnancy Childbirth. (2014) 14:1–9. doi: 10.1186/1471-239 et al. Changes of NK cells in preeclampsia. Am J Reprod Immunol. (2012) 3-14-306 67:278–86. doi: 10.1111/j.1600-0897.2012.01120.x 226. Zhang Y, Liu Z, Tian M, Hu X, Wang L, Ji J, et al. The altered PD- 239. Katano K, Suzuki S, Ozaki Y, Suzumori N, Kitaori T, Sugiura-Ogasawara 1/PD-L1 pathway delivers the ‘one-two punch’ eﬀects to promote the M. Peripheral natural killer cell activity as a predictor of recurrent Treg/Th17 imbalance in pre-eclampsia. Cell Mol Immunol. (2018) 15:710– pregnancy loss: a large cohort study. Fertil Steril. (2013) 100:1629–34. 23. doi: 10.1038/cmi.2017.70 doi: 10.1016/j.fertnstert.2013.07.1996 227. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, 240. Terme M, Chaput N, Combadiere B, Ma A, Ohteki T, Zitvogel L. Regulatory Kuchroo VK, et al. PD-L1 regulates the development, maintenance, and T cells control dendritic cell/NK cell cross-talk in lymph nodes at the function of induced regulatory T cells. J Exp Med. (2009) 206:3015–29. steady state by inhibiting CD4+ self-reactive T cells. J Immunol. (2008) doi: 10.1084/jem.20090847 180:4679–86. doi: 10.4049/jimmunol.180.7.4679 228. D’Addio F, Riella LV, Mfarrej BG, Chabtini L, Adams LT, Yeung M, et al. 241. Ghiringhelli F, Ménard C, Terme M, Flament C, Taieb J, Chaput N, et al. The link between the PDL1 costimulatory pathway and Th17 in fetomaternal CD4 CD25 regulatory T cells inhibit natural killer cell functions in a tolerance. J Immunol. (2011) 187:4530–41. doi: 10.4049/jimmunol.1002031 transforming growth factor-dependent manner. J Exp Med. (2005) 202:1075– 229. Wakkach A, Fournier N, Brun V, Breittmayer JP, Cottrez F, Groux 1085. doi: 10.1084/jem.20051511 H. Characterization of dendritic cells that induce tolerance and T 242. Keskin DB, Allan DSJ, Rybalov B, Andzelm MM, Stern JNH, Kopcow HD, regulatory 1 cell diﬀerentiation in vivo. Immunity. (2003) 18:605–17. et al. TGFbeta promotes conversion of CD16+ peripheral blood NK cells doi: 10.1016/S1074-7613(03)00113-4 into CD16- NK cells with similarities to decidual NK cells. Proc Natl Acad 230. Miyazaki S, Tsuda H, Sakai M, Hori S, Sasaki Y, Futatani T, et al. Sci USA. (2007) 104:3378–83. doi: 10.1073/pnas.0611098104 Predominance of Th2-promoting dendritic cells in early human pregnancy 243. Fu B, Li X, Sun R, Tong X, Ling B, Tian Z, et al. Natural killer cells decidua. J Leukoc Biol. (2003) 74:514–22. doi: 10.1189/jlb.1102566 promote immune tolerance by regulating inﬂammatory TH17 cells at the 231. Blois SM, Alba Soto CD, Tometten M, Klapp BF, Margni RA, Arck human maternal-fetal interface. Proc Natl Acad Sci USA. (2013) 110:E231– PC. Lineage, maturity, and phenotype of uterine murine dendritic cells 40. doi: 10.1073/pnas.1206322110 throughout gestation indicate a protective role in maintaining pregnancy. 244. Renaud SJ, Cotechini T, Quirt JS, Macdonald-Goodfellow SK, Othman M, Biol Reprod. (2004) 70:1018–23. doi: 10.1095/biolreprod.103.022640 Graham CH. Spontaneous pregnancy loss mediated by abnormal maternal 232. Tiemessen MM, van Herwijnen MJC, Evans HG, Jagger AL, Taams LS, John inﬂammation in rats is linked to deﬁcient uteroplacental perfusion. J S. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of Immunol. (2011) 186:1799–808. doi: 10.4049/jimmunol.1002679 human monocytes/macrophages. Proc Natl Acad Sci USA. (2007) 104:19446– 245. Heitmann RJ, Weitzel RP, Feng Y, Segars JH, Tisdale JF, Wolﬀ EF. Maternal 51. doi: 10.1073/pnas.0706832104 T regulatory cell depletion impairs embryo implantation which can be 233. Schumacher A, Wafula PO, Teles A, El-Mousleh T, Linzke N, corrected with adoptive T regulatory cell transfer. Reprod Sci. (2017) Zenclussen ML, et al. Blockage of heme oxygenase-1 abrogates the 24:1014–24. doi: 10.1177/1933719116675054 protective eﬀect of regulatory T cells on murine pregnancy and 246. Wilczynski JR, Kalinka J, Radwan M. The role of T-regulatory cells promotes the maturation of dendritic cells. PLoS ONE. (2012) 7:e42301. in pregnancy and cancer. Front Biosci. (2008) 13:2275–89. doi: 10.274 doi: 10.1371/journal.pone.0042301 1/2841 234. Mellor AL, Sivakumar J, Chandler P, Smith K, Molina H, Mao D, et al. Prevention of T cell-driven complement activation and inﬂammation by Conﬂict of Interest Statement: The authors declare that the research was tryptophan catabolism during pregnancy. Nat Immunol. (2001) 2:64–8. conducted in the absence of any commercial or ﬁnancial relationships that could doi: 10.1038/83183 be construed as a potential conﬂict of interest. 235. Vacca P, Cantoni C, Vitale M, Prato C, Canegallo F, Fenoglio D, et al. Crosstalk between decidual NK and CD14+ myelomonocytic cells results in Copyright © 2019 Jørgensen, Persson and Hviid. This is an open-access article induction of Tregs and immunosuppression. Proc Natl Acad Sci USA. (2010) distributed under the terms of the Creative Commons Attribution License (CC BY). 107:11918–23. doi: 10.1073/pnas.1001749107 The use, distribution or reproduction in other forums is permitted, provided the 236. Moﬀett A, Colucci F. Uterine NK cells: active regulators at the maternal-fetal original author(s) and the copyright owner(s) are credited and that the original interface. J Clin Invest. (2014) 124:1872–79. doi: 10.1172/JCI68107 publication in this journal is cited, in accordance with accepted academic practice. 237. Moﬀett-King A. Natural killer cells and pregnancy. Nat Rev Immunol. (2002) No use, distribution or reproduction is permitted which does not comply with these 2:656–63. doi: 10.1038/nri886 terms. Frontiers in Immunology | www.frontiersin.org 21 May 2019 | Volume 10 | Article 911

Journal

Frontiers in Immunology – Unpaywall

Published: May 8, 2019

Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer

The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer

Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer

The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer

References (256)

Abstract

Journal

Recommended Articles

There are no references for this article.

Our policy towards the use of cookies