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Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling

Notch receptors direct the differentiation of T helper (T(H)) cell subsets, but their influence on regulatory T (T(reg)) cell responses is obscure. We here report that lineage-specific deletion of components of the Notch pathway enhanced T(reg) cell-mediated suppression of T(H)1 responses, and prote...

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Autores principales: Charbonnier, Louis-Marie, Wang, Sen, Georgiev, Peter, Sefik, Esen, Chatila, Talal A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618075/
https://www.ncbi.nlm.nih.gov/pubmed/26437242
http://dx.doi.org/10.1038/ni.3288
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author Charbonnier, Louis-Marie
Wang, Sen
Georgiev, Peter
Sefik, Esen
Chatila, Talal A
author_facet Charbonnier, Louis-Marie
Wang, Sen
Georgiev, Peter
Sefik, Esen
Chatila, Talal A
author_sort Charbonnier, Louis-Marie
collection PubMed
description Notch receptors direct the differentiation of T helper (T(H)) cell subsets, but their influence on regulatory T (T(reg)) cell responses is obscure. We here report that lineage-specific deletion of components of the Notch pathway enhanced T(reg) cell-mediated suppression of T(H)1 responses, and protected against their T(H)1 skewing and apoptosis. Expression in T(reg) cells of gain of function transgene encoding Notch1 intracellular domain resulted in lymphoproliferation, exacerbated T(H)1 responses and autoimmunity. Cell-intrinsic canonical Notch signaling impaired T(reg) cell fitness, promoted the acquisition by T(reg) cells of a T(H)1 cell-like phenotype, whereas Rictor-dependent non-canonical Notch signaling activated the AKT-Foxo1 axis and impaired Foxp3 epigenetic stability. These findings establish a critical role for Notch signaling in controlling peripheral T(reg) cell functions.
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spelling pubmed-46180752016-05-01 Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling Charbonnier, Louis-Marie Wang, Sen Georgiev, Peter Sefik, Esen Chatila, Talal A Nat Immunol Article Notch receptors direct the differentiation of T helper (T(H)) cell subsets, but their influence on regulatory T (T(reg)) cell responses is obscure. We here report that lineage-specific deletion of components of the Notch pathway enhanced T(reg) cell-mediated suppression of T(H)1 responses, and protected against their T(H)1 skewing and apoptosis. Expression in T(reg) cells of gain of function transgene encoding Notch1 intracellular domain resulted in lymphoproliferation, exacerbated T(H)1 responses and autoimmunity. Cell-intrinsic canonical Notch signaling impaired T(reg) cell fitness, promoted the acquisition by T(reg) cells of a T(H)1 cell-like phenotype, whereas Rictor-dependent non-canonical Notch signaling activated the AKT-Foxo1 axis and impaired Foxp3 epigenetic stability. These findings establish a critical role for Notch signaling in controlling peripheral T(reg) cell functions. 2015-10-05 2015-11 /pmc/articles/PMC4618075/ /pubmed/26437242 http://dx.doi.org/10.1038/ni.3288 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Charbonnier, Louis-Marie
Wang, Sen
Georgiev, Peter
Sefik, Esen
Chatila, Talal A
Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling
title Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling
title_full Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling
title_fullStr Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling
title_full_unstemmed Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling
title_short Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling
title_sort control of peripheral tolerance by regulatory t cell-intrinsic notch signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618075/
https://www.ncbi.nlm.nih.gov/pubmed/26437242
http://dx.doi.org/10.1038/ni.3288
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