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Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8(+) T Cell Function

T cell receptors recognize small changes in peptide ligands leading to different T cell responses. Here, we analyzed a panel of HLA-A2–Tax11-19 reactive T cell clones to examine how small allelic variations of MHC molecules could alter the functional outcome of antigen recognition. Similar to the ef...

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Autores principales: Lim, Dong-Gyun, Slavik, Jacqueline M., Bourcier, Katarzyna, Smith, Kathrine J., Hafler, David A.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196091/
https://www.ncbi.nlm.nih.gov/pubmed/12847139
http://dx.doi.org/10.1084/jem.20021796
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author Lim, Dong-Gyun
Slavik, Jacqueline M.
Bourcier, Katarzyna
Smith, Kathrine J.
Hafler, David A.
author_facet Lim, Dong-Gyun
Slavik, Jacqueline M.
Bourcier, Katarzyna
Smith, Kathrine J.
Hafler, David A.
author_sort Lim, Dong-Gyun
collection PubMed
description T cell receptors recognize small changes in peptide ligands leading to different T cell responses. Here, we analyzed a panel of HLA-A2–Tax11-19 reactive T cell clones to examine how small allelic variations of MHC molecules could alter the functional outcome of antigen recognition. Similar to the effects induced by antigenic altered peptide ligands, weak or partial agonistic T cell functions were identified in individual T cell clones with the recognition of MHC-altered peptide ligands (MAPLs). Interestingly, one subtype of HLA-A2 molecules induced an unusual type of partial agonistic function; proliferation without cytotoxicity. Modeling of crystallographic data indicated that polymorphic amino acids in the HLA-A2 peptide binding groove, especially the D-pocket, were responsible for this partial agonism. Reciprocal mutations of the Tax peptide side chain engaging the D-pocket indeed restored the agonist functions of the MHC–peptide complex. Whereas early intracellular signaling events were not efficiently induced by these MAPLs, phosphorylated c-Jun slowly accumulated with sustained long-term expression. These data indicate that MAPLs can induce atypical partial agonistic T cell function through structural and biochemical mechanisms similar to altered peptide ligands.
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spelling pubmed-21960912008-04-11 Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8(+) T Cell Function Lim, Dong-Gyun Slavik, Jacqueline M. Bourcier, Katarzyna Smith, Kathrine J. Hafler, David A. J Exp Med Article T cell receptors recognize small changes in peptide ligands leading to different T cell responses. Here, we analyzed a panel of HLA-A2–Tax11-19 reactive T cell clones to examine how small allelic variations of MHC molecules could alter the functional outcome of antigen recognition. Similar to the effects induced by antigenic altered peptide ligands, weak or partial agonistic T cell functions were identified in individual T cell clones with the recognition of MHC-altered peptide ligands (MAPLs). Interestingly, one subtype of HLA-A2 molecules induced an unusual type of partial agonistic function; proliferation without cytotoxicity. Modeling of crystallographic data indicated that polymorphic amino acids in the HLA-A2 peptide binding groove, especially the D-pocket, were responsible for this partial agonism. Reciprocal mutations of the Tax peptide side chain engaging the D-pocket indeed restored the agonist functions of the MHC–peptide complex. Whereas early intracellular signaling events were not efficiently induced by these MAPLs, phosphorylated c-Jun slowly accumulated with sustained long-term expression. These data indicate that MAPLs can induce atypical partial agonistic T cell function through structural and biochemical mechanisms similar to altered peptide ligands. The Rockefeller University Press 2003-07-07 /pmc/articles/PMC2196091/ /pubmed/12847139 http://dx.doi.org/10.1084/jem.20021796 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Lim, Dong-Gyun
Slavik, Jacqueline M.
Bourcier, Katarzyna
Smith, Kathrine J.
Hafler, David A.
Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8(+) T Cell Function
title Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8(+) T Cell Function
title_full Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8(+) T Cell Function
title_fullStr Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8(+) T Cell Function
title_full_unstemmed Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8(+) T Cell Function
title_short Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8(+) T Cell Function
title_sort allelic variation of mhc structure alters peptide ligands to induce atypical partial agonistic cd8(+) t cell function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196091/
https://www.ncbi.nlm.nih.gov/pubmed/12847139
http://dx.doi.org/10.1084/jem.20021796
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