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The AKT–mTOR axis regulates de novo differentiation of CD4(+)Foxp3(+) cells

CD4(+)Foxp3(+) regulatory T (T reg) cells play an essential role in maintaining immunological tolerance via their suppressive function on conventional CD4(+) T (Tconv) cells. Repertoire studies suggest that distinct T cell receptor signaling pathways lead to T reg differentiation, but the signals th...

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Detalles Bibliográficos
Autores principales: Haxhinasto, Sokol, Mathis, Diane, Benoist, Christophe
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275380/
https://www.ncbi.nlm.nih.gov/pubmed/18283119
http://dx.doi.org/10.1084/jem.20071477
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author Haxhinasto, Sokol
Mathis, Diane
Benoist, Christophe
author_facet Haxhinasto, Sokol
Mathis, Diane
Benoist, Christophe
author_sort Haxhinasto, Sokol
collection PubMed
description CD4(+)Foxp3(+) regulatory T (T reg) cells play an essential role in maintaining immunological tolerance via their suppressive function on conventional CD4(+) T (Tconv) cells. Repertoire studies suggest that distinct T cell receptor signaling pathways lead to T reg differentiation, but the signals that regulate T reg specification are largely unknown. We identify AKT as a strong repressor of entry into the T reg phenotype in vitro and in vivo. A constitutively active allele of AKT substantially diminished TGF-β–induced Foxp3 expression in a kinase-dependent manner and via a rapamycin-sensitive pathway, implicating the AKT–mammalian target of rapamycin axis. The observed impairment in Foxp3 induction was part of a broad dampening of the typical T reg transcriptional signature. Expression of active AKT at a stage before Foxp3 turn on during normal T reg differentiation in the thymus selectively impaired differentiation of CD4(+)Foxp3(+) cells without any alteration in the positive selection of Tconv. Activated AKT, in contrast, did not affect established Foxp3 expression in T reg cells. These results place AKT at a nexus of signaling pathways whose proper activation has a strong and broad impact on the onset of T reg specification.
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spelling pubmed-22753802008-09-17 The AKT–mTOR axis regulates de novo differentiation of CD4(+)Foxp3(+) cells Haxhinasto, Sokol Mathis, Diane Benoist, Christophe J Exp Med Articles CD4(+)Foxp3(+) regulatory T (T reg) cells play an essential role in maintaining immunological tolerance via their suppressive function on conventional CD4(+) T (Tconv) cells. Repertoire studies suggest that distinct T cell receptor signaling pathways lead to T reg differentiation, but the signals that regulate T reg specification are largely unknown. We identify AKT as a strong repressor of entry into the T reg phenotype in vitro and in vivo. A constitutively active allele of AKT substantially diminished TGF-β–induced Foxp3 expression in a kinase-dependent manner and via a rapamycin-sensitive pathway, implicating the AKT–mammalian target of rapamycin axis. The observed impairment in Foxp3 induction was part of a broad dampening of the typical T reg transcriptional signature. Expression of active AKT at a stage before Foxp3 turn on during normal T reg differentiation in the thymus selectively impaired differentiation of CD4(+)Foxp3(+) cells without any alteration in the positive selection of Tconv. Activated AKT, in contrast, did not affect established Foxp3 expression in T reg cells. These results place AKT at a nexus of signaling pathways whose proper activation has a strong and broad impact on the onset of T reg specification. The Rockefeller University Press 2008-03-17 /pmc/articles/PMC2275380/ /pubmed/18283119 http://dx.doi.org/10.1084/jem.20071477 Text en Copyright © 2008, 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 Articles
Haxhinasto, Sokol
Mathis, Diane
Benoist, Christophe
The AKT–mTOR axis regulates de novo differentiation of CD4(+)Foxp3(+) cells
title The AKT–mTOR axis regulates de novo differentiation of CD4(+)Foxp3(+) cells
title_full The AKT–mTOR axis regulates de novo differentiation of CD4(+)Foxp3(+) cells
title_fullStr The AKT–mTOR axis regulates de novo differentiation of CD4(+)Foxp3(+) cells
title_full_unstemmed The AKT–mTOR axis regulates de novo differentiation of CD4(+)Foxp3(+) cells
title_short The AKT–mTOR axis regulates de novo differentiation of CD4(+)Foxp3(+) cells
title_sort akt–mtor axis regulates de novo differentiation of cd4(+)foxp3(+) cells
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275380/
https://www.ncbi.nlm.nih.gov/pubmed/18283119
http://dx.doi.org/10.1084/jem.20071477
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