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Self-reactive human CD4 T cell clones form unusual immunological synapses

Recognition of self–peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases. We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes. All self-reactive T...

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Autores principales: Schubert, David A., Gordo, Susana, Sabatino, Joseph J., Vardhana, Santosh, Gagnon, Etienne, Sethi, Dhruv K., Seth, Nilufer P., Choudhuri, Kaushik, Reijonen, Helena, Nepom, Gerald T., Evavold, Brian D., Dustin, Michael L., Wucherpfennig, Kai W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280872/
https://www.ncbi.nlm.nih.gov/pubmed/22312112
http://dx.doi.org/10.1084/jem.20111485
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author Schubert, David A.
Gordo, Susana
Sabatino, Joseph J.
Vardhana, Santosh
Gagnon, Etienne
Sethi, Dhruv K.
Seth, Nilufer P.
Choudhuri, Kaushik
Reijonen, Helena
Nepom, Gerald T.
Evavold, Brian D.
Dustin, Michael L.
Wucherpfennig, Kai W.
author_facet Schubert, David A.
Gordo, Susana
Sabatino, Joseph J.
Vardhana, Santosh
Gagnon, Etienne
Sethi, Dhruv K.
Seth, Nilufer P.
Choudhuri, Kaushik
Reijonen, Helena
Nepom, Gerald T.
Evavold, Brian D.
Dustin, Michael L.
Wucherpfennig, Kai W.
author_sort Schubert, David A.
collection PubMed
description Recognition of self–peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases. We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes. All self-reactive T cells contained a large number of phosphorylated T cell receptor (TCR) microclusters, indicative of active TCR signaling. However, they showed little or no visible pMHC accumulation or transport of TCR–pMHC complexes into a central supramolecular activation cluster (cSMAC). In contrast, influenza-specific T cells accumulated large quantities of pMHC complexes in microclusters and a cSMAC, even when presented with 100-fold lower pMHC densities. The self-reactive T cells also maintained a high degree of motility, again in sharp contrast to virus-specific T cells. 2D affinity measurements of three of these self-reactive T cell clones demonstrated a normal off-rate but a slow on-rate of TCR binding to pMHC. These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus. However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease.
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spelling pubmed-32808722012-08-13 Self-reactive human CD4 T cell clones form unusual immunological synapses Schubert, David A. Gordo, Susana Sabatino, Joseph J. Vardhana, Santosh Gagnon, Etienne Sethi, Dhruv K. Seth, Nilufer P. Choudhuri, Kaushik Reijonen, Helena Nepom, Gerald T. Evavold, Brian D. Dustin, Michael L. Wucherpfennig, Kai W. J Exp Med Article Recognition of self–peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases. We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes. All self-reactive T cells contained a large number of phosphorylated T cell receptor (TCR) microclusters, indicative of active TCR signaling. However, they showed little or no visible pMHC accumulation or transport of TCR–pMHC complexes into a central supramolecular activation cluster (cSMAC). In contrast, influenza-specific T cells accumulated large quantities of pMHC complexes in microclusters and a cSMAC, even when presented with 100-fold lower pMHC densities. The self-reactive T cells also maintained a high degree of motility, again in sharp contrast to virus-specific T cells. 2D affinity measurements of three of these self-reactive T cell clones demonstrated a normal off-rate but a slow on-rate of TCR binding to pMHC. These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus. However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease. The Rockefeller University Press 2012-02-13 /pmc/articles/PMC3280872/ /pubmed/22312112 http://dx.doi.org/10.1084/jem.20111485 Text en © 2012 Schubert et al. 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 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Schubert, David A.
Gordo, Susana
Sabatino, Joseph J.
Vardhana, Santosh
Gagnon, Etienne
Sethi, Dhruv K.
Seth, Nilufer P.
Choudhuri, Kaushik
Reijonen, Helena
Nepom, Gerald T.
Evavold, Brian D.
Dustin, Michael L.
Wucherpfennig, Kai W.
Self-reactive human CD4 T cell clones form unusual immunological synapses
title Self-reactive human CD4 T cell clones form unusual immunological synapses
title_full Self-reactive human CD4 T cell clones form unusual immunological synapses
title_fullStr Self-reactive human CD4 T cell clones form unusual immunological synapses
title_full_unstemmed Self-reactive human CD4 T cell clones form unusual immunological synapses
title_short Self-reactive human CD4 T cell clones form unusual immunological synapses
title_sort self-reactive human cd4 t cell clones form unusual immunological synapses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280872/
https://www.ncbi.nlm.nih.gov/pubmed/22312112
http://dx.doi.org/10.1084/jem.20111485
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