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Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells

Thymus-derived (natural) CD4(+) FoxP3(+) regulatory T cells (nT reg cells) are required for immune homeostasis and self-tolerance, but must be stringently controlled to permit expansion of protective immunity. Previous findings linking signals transmitted through T cell–expressed C5a receptor (C5aR)...

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Autores principales: Kwan, Wing-hong, van der Touw, William, Paz-Artal, Estela, Li, Ming O., Heeger, Peter S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570105/
https://www.ncbi.nlm.nih.gov/pubmed/23382542
http://dx.doi.org/10.1084/jem.20121525
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author Kwan, Wing-hong
van der Touw, William
Paz-Artal, Estela
Li, Ming O.
Heeger, Peter S.
author_facet Kwan, Wing-hong
van der Touw, William
Paz-Artal, Estela
Li, Ming O.
Heeger, Peter S.
author_sort Kwan, Wing-hong
collection PubMed
description Thymus-derived (natural) CD4(+) FoxP3(+) regulatory T cells (nT reg cells) are required for immune homeostasis and self-tolerance, but must be stringently controlled to permit expansion of protective immunity. Previous findings linking signals transmitted through T cell–expressed C5a receptor (C5aR) and C3a receptor (C3aR) to activation, differentiation, and expansion of conventional CD4(+)CD25(−) T cells (T conv cells), raised the possibility that C3aR/C5aR signaling on nT reg cells could physiologically modulate nT reg cell function and thereby further impact the induced strength of T cell immune responses. In this study, we demonstrate that nT reg cells express C3aR and C5aR, and that signaling through these receptors inhibits nT reg cell function. Genetic and pharmacological blockade of C3aR/C5aR signal transduction in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival. Mechanisms involve C3a/C5a-induced phosphorylation of AKT and, as a consequence, phosphorylation of the transcription factor Foxo1, which results in lowered nT reg cell Foxp3 expression. The documentation that C3a/C3aR and C5a/C5aR modulate nT reg cell function via controlling Foxp3 expression suggests targeting this pathway could be exploited to manipulate pathogenic or protective T cell responses.
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spelling pubmed-35701052013-08-11 Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells Kwan, Wing-hong van der Touw, William Paz-Artal, Estela Li, Ming O. Heeger, Peter S. J Exp Med Article Thymus-derived (natural) CD4(+) FoxP3(+) regulatory T cells (nT reg cells) are required for immune homeostasis and self-tolerance, but must be stringently controlled to permit expansion of protective immunity. Previous findings linking signals transmitted through T cell–expressed C5a receptor (C5aR) and C3a receptor (C3aR) to activation, differentiation, and expansion of conventional CD4(+)CD25(−) T cells (T conv cells), raised the possibility that C3aR/C5aR signaling on nT reg cells could physiologically modulate nT reg cell function and thereby further impact the induced strength of T cell immune responses. In this study, we demonstrate that nT reg cells express C3aR and C5aR, and that signaling through these receptors inhibits nT reg cell function. Genetic and pharmacological blockade of C3aR/C5aR signal transduction in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival. Mechanisms involve C3a/C5a-induced phosphorylation of AKT and, as a consequence, phosphorylation of the transcription factor Foxo1, which results in lowered nT reg cell Foxp3 expression. The documentation that C3a/C3aR and C5a/C5aR modulate nT reg cell function via controlling Foxp3 expression suggests targeting this pathway could be exploited to manipulate pathogenic or protective T cell responses. The Rockefeller University Press 2013-02-11 /pmc/articles/PMC3570105/ /pubmed/23382542 http://dx.doi.org/10.1084/jem.20121525 Text en © 2013 Kwan 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
Kwan, Wing-hong
van der Touw, William
Paz-Artal, Estela
Li, Ming O.
Heeger, Peter S.
Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells
title Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells
title_full Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells
title_fullStr Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells
title_full_unstemmed Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells
title_short Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells
title_sort signaling through c5a receptor and c3a receptor diminishes function of murine natural regulatory t cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570105/
https://www.ncbi.nlm.nih.gov/pubmed/23382542
http://dx.doi.org/10.1084/jem.20121525
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