Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor

The T cell receptor (TCR) is a versatile receptor able to generate different signals that result in distinct T cell responses. The pattern of early signals is determined by the TCR binding kinetics that control the ability of the ligand to coengage TCR and coreceptor. Coengagement of TCR and CD4 res...

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Main Authors: Chau, Luan A., Bluestone, Jeffrey A., Madrenas, Joaquín
Formato: Artigo
Idioma:English
Publicado em: The Rockefeller University Press 1998
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Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC2212283/
https://ncbi.nlm.nih.gov/pubmed/9584148
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spelling pubmed-22122832008-04-16 Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor Chau, Luan A. Bluestone, Jeffrey A. Madrenas, Joaquín J Exp Med Article The T cell receptor (TCR) is a versatile receptor able to generate different signals that result in distinct T cell responses. The pattern of early signals is determined by the TCR binding kinetics that control the ability of the ligand to coengage TCR and coreceptor. Coengagement of TCR and CD4 results in an agonist signaling pattern with complete tyrosine phosphorylation of TCR subunits, and recruitment and activation of ZAP-70. In contrast, TCR engagement without CD4 coengagement causes a partial agonist type of signaling, characterized by distinct phosphorylation of TCR subunits and recruitment but no activation of ZAP-70. The pathways triggered by partial agonist signaling are unknown. Here, we show that agonists cause association of active lck and active ZAP-70 with p120-GTPase–activating protein (p120-GAP). These associations follow engagement of CD4 or CD3, respectively. In contrast, partial agonists do not activate lck or ZAP-70, but induce association of p120-GAP with inactive ZAP-70. Despite these differences, both agonist and partial agonist signals activate the mitogen-activated protein kinase (MAPK) pathway. However, MAPK activation by partial agonists is transient, supporting a kinetic, CD4-dependent model for the mechanism of action of variant TCR ligands. Transient MAPK activation may explain some of the responses to TCR partial agonists and antagonists. The Rockefeller University Press 1998-05-18 /pmc/articles/PMC2212283/ /pubmed/9584148 Text en 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/).
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Article
spellingShingle Article
Chau, Luan A.
Bluestone, Jeffrey A.
Madrenas, Joaquín
Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor
description The T cell receptor (TCR) is a versatile receptor able to generate different signals that result in distinct T cell responses. The pattern of early signals is determined by the TCR binding kinetics that control the ability of the ligand to coengage TCR and coreceptor. Coengagement of TCR and CD4 results in an agonist signaling pattern with complete tyrosine phosphorylation of TCR subunits, and recruitment and activation of ZAP-70. In contrast, TCR engagement without CD4 coengagement causes a partial agonist type of signaling, characterized by distinct phosphorylation of TCR subunits and recruitment but no activation of ZAP-70. The pathways triggered by partial agonist signaling are unknown. Here, we show that agonists cause association of active lck and active ZAP-70 with p120-GTPase–activating protein (p120-GAP). These associations follow engagement of CD4 or CD3, respectively. In contrast, partial agonists do not activate lck or ZAP-70, but induce association of p120-GAP with inactive ZAP-70. Despite these differences, both agonist and partial agonist signals activate the mitogen-activated protein kinase (MAPK) pathway. However, MAPK activation by partial agonists is transient, supporting a kinetic, CD4-dependent model for the mechanism of action of variant TCR ligands. Transient MAPK activation may explain some of the responses to TCR partial agonists and antagonists.
author Chau, Luan A.
Bluestone, Jeffrey A.
Madrenas, Joaquín
author_facet Chau, Luan A.
Bluestone, Jeffrey A.
Madrenas, Joaquín
author_sort Chau, Luan A.
title Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor
title_short Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor
title_full Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor
title_fullStr Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor
title_full_unstemmed Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor
title_sort dissociation of intracellular signaling pathways in response to partial agonist ligands of the t cell receptor
publisher The Rockefeller University Press
publisher_facet The Rockefeller University Press
publishDate 1998
url https://ncbi.nlm.nih.gov/pmc/articles/PMC2212283/
https://ncbi.nlm.nih.gov/pubmed/9584148
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