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The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development

CD4(+) regulatory T cells (T(reg) cells) expressing the transcription factor Foxp3 play a pivotal role in maintaining peripheral tolerance by inhibiting the expansion and function of pathogenic conventional T cells (T(conv) cells). In this study, we show that a locus on rat chromosome 9 controls the...

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Autores principales: Colacios, Céline, Casemayou, Audrey, Dejean, Anne S., Gaits-Iacovoni, Frédérique, Pedros, Christophe, Bernard, Isabelle, Lagrange, Dominique, Deckert, Marcel, Lamouroux, Lucille, Jagodic, Maja, Olsson, Tomas, Liblau, Roland S., Fournié, Gilbert J., Saoudi, Abdelhadi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201202/
https://www.ncbi.nlm.nih.gov/pubmed/21948080
http://dx.doi.org/10.1084/jem.20102191
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author Colacios, Céline
Casemayou, Audrey
Dejean, Anne S.
Gaits-Iacovoni, Frédérique
Pedros, Christophe
Bernard, Isabelle
Lagrange, Dominique
Deckert, Marcel
Lamouroux, Lucille
Jagodic, Maja
Olsson, Tomas
Liblau, Roland S.
Fournié, Gilbert J.
Saoudi, Abdelhadi
author_facet Colacios, Céline
Casemayou, Audrey
Dejean, Anne S.
Gaits-Iacovoni, Frédérique
Pedros, Christophe
Bernard, Isabelle
Lagrange, Dominique
Deckert, Marcel
Lamouroux, Lucille
Jagodic, Maja
Olsson, Tomas
Liblau, Roland S.
Fournié, Gilbert J.
Saoudi, Abdelhadi
author_sort Colacios, Céline
collection PubMed
description CD4(+) regulatory T cells (T(reg) cells) expressing the transcription factor Foxp3 play a pivotal role in maintaining peripheral tolerance by inhibiting the expansion and function of pathogenic conventional T cells (T(conv) cells). In this study, we show that a locus on rat chromosome 9 controls the size of the natural T(reg) cell compartment. Fine mapping of this locus with interval-specific congenic lines and association experiments using single nucleotide polymorphisms (SNPs) identified a nonsynonymous SNP in the Vav1 gene that leads to the substitution of an arginine by a tryptophan (p.Arg63Trp). This p.Arg63Trp polymorphism is associated with increased proportion and absolute numbers of T(reg) cells in the thymus and peripheral lymphoid organs, without impacting the size of the T(conv) cell compartment. This polymorphism is also responsible for Vav1 constitutive activation, revealed by its tyrosine 174 hyperphosphorylation and increased guanine nucleotide exchange factor activity. Moreover, it induces a marked reduction in Vav1 cellular contents and a reduction of Ca(2+) flux after TCR engagement. Together, our data reveal a key role for Vav1-dependent T cell antigen receptor signaling in natural T(reg) cell development.
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spelling pubmed-32012022012-04-24 The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development Colacios, Céline Casemayou, Audrey Dejean, Anne S. Gaits-Iacovoni, Frédérique Pedros, Christophe Bernard, Isabelle Lagrange, Dominique Deckert, Marcel Lamouroux, Lucille Jagodic, Maja Olsson, Tomas Liblau, Roland S. Fournié, Gilbert J. Saoudi, Abdelhadi J Exp Med Brief Definitive Report CD4(+) regulatory T cells (T(reg) cells) expressing the transcription factor Foxp3 play a pivotal role in maintaining peripheral tolerance by inhibiting the expansion and function of pathogenic conventional T cells (T(conv) cells). In this study, we show that a locus on rat chromosome 9 controls the size of the natural T(reg) cell compartment. Fine mapping of this locus with interval-specific congenic lines and association experiments using single nucleotide polymorphisms (SNPs) identified a nonsynonymous SNP in the Vav1 gene that leads to the substitution of an arginine by a tryptophan (p.Arg63Trp). This p.Arg63Trp polymorphism is associated with increased proportion and absolute numbers of T(reg) cells in the thymus and peripheral lymphoid organs, without impacting the size of the T(conv) cell compartment. This polymorphism is also responsible for Vav1 constitutive activation, revealed by its tyrosine 174 hyperphosphorylation and increased guanine nucleotide exchange factor activity. Moreover, it induces a marked reduction in Vav1 cellular contents and a reduction of Ca(2+) flux after TCR engagement. Together, our data reveal a key role for Vav1-dependent T cell antigen receptor signaling in natural T(reg) cell development. The Rockefeller University Press 2011-10-24 /pmc/articles/PMC3201202/ /pubmed/21948080 http://dx.doi.org/10.1084/jem.20102191 Text en © 2011 Colacios 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 Brief Definitive Report
Colacios, Céline
Casemayou, Audrey
Dejean, Anne S.
Gaits-Iacovoni, Frédérique
Pedros, Christophe
Bernard, Isabelle
Lagrange, Dominique
Deckert, Marcel
Lamouroux, Lucille
Jagodic, Maja
Olsson, Tomas
Liblau, Roland S.
Fournié, Gilbert J.
Saoudi, Abdelhadi
The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development
title The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development
title_full The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development
title_fullStr The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development
title_full_unstemmed The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development
title_short The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development
title_sort p.arg63trp polymorphism controls vav1 functions and foxp3 regulatory t cell development
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201202/
https://www.ncbi.nlm.nih.gov/pubmed/21948080
http://dx.doi.org/10.1084/jem.20102191
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