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Major histocompatibility complex regulation of T helper functions mapped to a peptide C terminus that controls ligand density

Major histocompatibility complex regulation of T helper functions mapped to a peptide C terminus... The functional status (Th1‐ versus Th2‐like) of CD4 T cells primed against human collagen type IV (hCol IV) or a single 30mer peptide from the α2 chain of this molecule is predicted by the major histocompatibility complex (MHC) class II (I‐A) genotype of the responding mice. H‐2s mice elicit Th1‐like cell‐mediated responses to these antigens, whereas Th2‐like humoral responses are primed in H‐2b,d,k mice. We now report that the ability of MHC to dictate T helper function in this system depends upon a single amino acid of the minimal α2(IV) peptide. The C terminus of this minimal (12mer) peptide is ‐G‐G‐P‐K, which is predicted to form a β‐turn. The present data demonstrate that the terminal lysine (K) stabilizes the immunogens full biological effects necessary for exclusive cellmediated responses in H‐2s mice. The lysine‐truncated (11mer) peptide with otherwise identical sequence effectively primes T helper function in both H‐2b and H‐2s genotypes. Most importantly, our direct analysis of these peptides' presentation by live antigen‐presenting cells (APC) reveals that the 12mer is bound at a log higher density on H‐2s APC than on H‐2b APC, and that the 11mer is presented at an equally low relative density on APC from both genotypes. In vitro analyses of 12mer/11mer cross‐reactive Th clones demonstrate that I‐As restricted clones require about 1–2 log lower doses of 12mer peptide than 11mer peptide to stimulate equivalent thymidine incorporation and cytokine release. By contrast, I‐Ab‐restricted (12mer/11mer cross‐reactive) Th clones show no preference for the 12mer and require relatively high peptide doses similar to those required to stimulate the I‐As clones with the 11mer peptide. Thus, the peptide dose requirements of Th clones reflect the high density of presentation associated with the 12mer: I‐As ligand. Taken together, the results directly support the role of ligand density as an important control point in the functional decision of CD4 T cells. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Immunology Wiley

Major histocompatibility complex regulation of T helper functions mapped to a peptide C terminus that controls ligand density

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References (50)

Publisher
Wiley
Copyright
Copyright © 1994 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim
ISSN
0014-2980
eISSN
1521-4141
DOI
10.1002/eji.1830241012
pmid
7925562
Publisher site
See Article on Publisher Site

Abstract

The functional status (Th1‐ versus Th2‐like) of CD4 T cells primed against human collagen type IV (hCol IV) or a single 30mer peptide from the α2 chain of this molecule is predicted by the major histocompatibility complex (MHC) class II (I‐A) genotype of the responding mice. H‐2s mice elicit Th1‐like cell‐mediated responses to these antigens, whereas Th2‐like humoral responses are primed in H‐2b,d,k mice. We now report that the ability of MHC to dictate T helper function in this system depends upon a single amino acid of the minimal α2(IV) peptide. The C terminus of this minimal (12mer) peptide is ‐G‐G‐P‐K, which is predicted to form a β‐turn. The present data demonstrate that the terminal lysine (K) stabilizes the immunogens full biological effects necessary for exclusive cellmediated responses in H‐2s mice. The lysine‐truncated (11mer) peptide with otherwise identical sequence effectively primes T helper function in both H‐2b and H‐2s genotypes. Most importantly, our direct analysis of these peptides' presentation by live antigen‐presenting cells (APC) reveals that the 12mer is bound at a log higher density on H‐2s APC than on H‐2b APC, and that the 11mer is presented at an equally low relative density on APC from both genotypes. In vitro analyses of 12mer/11mer cross‐reactive Th clones demonstrate that I‐As restricted clones require about 1–2 log lower doses of 12mer peptide than 11mer peptide to stimulate equivalent thymidine incorporation and cytokine release. By contrast, I‐Ab‐restricted (12mer/11mer cross‐reactive) Th clones show no preference for the 12mer and require relatively high peptide doses similar to those required to stimulate the I‐As clones with the 11mer peptide. Thus, the peptide dose requirements of Th clones reflect the high density of presentation associated with the 12mer: I‐As ligand. Taken together, the results directly support the role of ligand density as an important control point in the functional decision of CD4 T cells.

Journal

European Journal of Immunology – Wiley

Published: Oct 1, 1994

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