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Fuel feeds function: energy metabolism and the T-cell response

Fuel feeds function: energy metabolism and the T-cell response For all cells, a constant supply of intracellular metabolites is required to sustain the most vital tasks of the cell. Nutrients such as glucose, amino acids and fatty acids can be degraded into simpler intermediates to provide metabolic energy in the form of ATP. The same intermediates can be used to build macromolecules such as proteins and lipids at the expense of ATP. In the peripheral circulation, glucose, amino acids and fatty acids are maintained at relatively constant concentrations. In the absence of instructional extracellular signals that are delivered through the ligation of cytokine, antigen or co-stimulatory receptors, lymphocytes lack the ability to take up sufficient nutrients to maintain even their basic bioenergetic needs. T cells have evolved the capacity to switch between states of relative quiescence and rapid proliferative expansion. These two fates are regulated, in part, by signals that are delivered through cytokine and antigen receptors, the outcome of which is closely coupled to the differentiation state of the responding cell. Rather than a default response to a lack of mitogenic signals, quiescence in T cells is an actively maintained state with unique metabolic demands. Resting T cells derive most of their ATP from the oxidative phosphorylation of intracellular metabolites, and they use this energy to suppress actively the expression of cell-cycle proteins through regulated protein degradation. Although activated lymphocytes are preparing to commit to the energy-demanding process of proliferation, they hyperinduce glycolysis and preferentially excrete pyruvate as lactate, even when oxygen is not present in limiting concentrations. This indicates that glucose uptake and utilization is a required part of the metabolic response of T cells to mitogenic signals. Rapamycin, which inhibits TOR (target of rapamycin), is a powerful immunosuppressant that functions by targeting cellular metabolism. In addition to enzymes of the phosphatidylinositol-3-kinase pathway, the kinases PIM1 and PIM2 are important contributors to the rapamycin sensitivity of lymphocytes in vivo and in vitro. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Immunology Springer Journals

Fuel feeds function: energy metabolism and the T-cell response

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References (107)

Publisher
Springer Journals
Copyright
Copyright © 2005 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Immunology
ISSN
1474-1733
eISSN
1474-1741
DOI
10.1038/nri1710
Publisher site
See Article on Publisher Site

Abstract

For all cells, a constant supply of intracellular metabolites is required to sustain the most vital tasks of the cell. Nutrients such as glucose, amino acids and fatty acids can be degraded into simpler intermediates to provide metabolic energy in the form of ATP. The same intermediates can be used to build macromolecules such as proteins and lipids at the expense of ATP. In the peripheral circulation, glucose, amino acids and fatty acids are maintained at relatively constant concentrations. In the absence of instructional extracellular signals that are delivered through the ligation of cytokine, antigen or co-stimulatory receptors, lymphocytes lack the ability to take up sufficient nutrients to maintain even their basic bioenergetic needs. T cells have evolved the capacity to switch between states of relative quiescence and rapid proliferative expansion. These two fates are regulated, in part, by signals that are delivered through cytokine and antigen receptors, the outcome of which is closely coupled to the differentiation state of the responding cell. Rather than a default response to a lack of mitogenic signals, quiescence in T cells is an actively maintained state with unique metabolic demands. Resting T cells derive most of their ATP from the oxidative phosphorylation of intracellular metabolites, and they use this energy to suppress actively the expression of cell-cycle proteins through regulated protein degradation. Although activated lymphocytes are preparing to commit to the energy-demanding process of proliferation, they hyperinduce glycolysis and preferentially excrete pyruvate as lactate, even when oxygen is not present in limiting concentrations. This indicates that glucose uptake and utilization is a required part of the metabolic response of T cells to mitogenic signals. Rapamycin, which inhibits TOR (target of rapamycin), is a powerful immunosuppressant that functions by targeting cellular metabolism. In addition to enzymes of the phosphatidylinositol-3-kinase pathway, the kinases PIM1 and PIM2 are important contributors to the rapamycin sensitivity of lymphocytes in vivo and in vitro.

Journal

Nature Reviews Immunology – Springer Journals

Published: Oct 20, 2005

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