Transiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.

Regulatory T-cells (Tregs) are central for immune homeostasis and divided in thymus-derived natural Tregs and peripherally induced iTreg. However, while phenotype and function of iTregs are well known, a remarkable lack exists in knowledge about signaling mechanisms leading to their generation from...

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Autores principales:	Eloho Etemire, Marco Krull, Mike Hasenberg, Peter Reichardt, Matthias Gunzer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fa839ddb567e4b34a08d2d6690bfdd3a
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spelling	oai:doaj.org-article:fa839ddb567e4b34a08d2d6690bfdd3a2021-11-18T07:37:50ZTransiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.1932-620310.1371/journal.pone.0068378https://doaj.org/article/fa839ddb567e4b34a08d2d6690bfdd3a2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874604/?tool=EBIhttps://doaj.org/toc/1932-6203Regulatory T-cells (Tregs) are central for immune homeostasis and divided in thymus-derived natural Tregs and peripherally induced iTreg. However, while phenotype and function of iTregs are well known, a remarkable lack exists in knowledge about signaling mechanisms leading to their generation from naïve precursors in peripheral tissues. Using antigen specific naïve T-cells from mice, we investigated CD4+ CD25+ FoxP3- iTreg induction during antigen-specific T-cell receptor (TCR) stimulation with weak antigen presenting cells (APC). We show that early signaling pathways such as ADAM-17-activation appeared similar in developing iTreg and effector cells (Teff) and both initially shedded CD62-L. But iTreg started reexpressing CD62-L after 24 h while Teff permanently downmodulated it. Furthermore, between 24 and 72 hours iTreg presented with significantly lower phosphorylation levels of Akt-S473 suggesting lower activity of the PI3K/Akt-axis. This was associated with a higher expression of the Akt hydrophobic motif-specific phosphatase PHLPP1 in iTreg. Importantly, the lack of costimulatory signals via CD28 from weak APC was central for the development of regulatory function in iTreg but not for the reappearance of CD62-L. Thus, T-cells display a window of sensitivity after onset of TCR triggering within which the intensity of the PI3K/Akt signal controls entry into either effector or regulatory pathways.Eloho EtemireMarco KrullMike HasenbergPeter ReichardtMatthias GunzerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e68378 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Eloho Etemire Marco Krull Mike Hasenberg Peter Reichardt Matthias Gunzer Transiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.
description	Regulatory T-cells (Tregs) are central for immune homeostasis and divided in thymus-derived natural Tregs and peripherally induced iTreg. However, while phenotype and function of iTregs are well known, a remarkable lack exists in knowledge about signaling mechanisms leading to their generation from naïve precursors in peripheral tissues. Using antigen specific naïve T-cells from mice, we investigated CD4+ CD25+ FoxP3- iTreg induction during antigen-specific T-cell receptor (TCR) stimulation with weak antigen presenting cells (APC). We show that early signaling pathways such as ADAM-17-activation appeared similar in developing iTreg and effector cells (Teff) and both initially shedded CD62-L. But iTreg started reexpressing CD62-L after 24 h while Teff permanently downmodulated it. Furthermore, between 24 and 72 hours iTreg presented with significantly lower phosphorylation levels of Akt-S473 suggesting lower activity of the PI3K/Akt-axis. This was associated with a higher expression of the Akt hydrophobic motif-specific phosphatase PHLPP1 in iTreg. Importantly, the lack of costimulatory signals via CD28 from weak APC was central for the development of regulatory function in iTreg but not for the reappearance of CD62-L. Thus, T-cells display a window of sensitivity after onset of TCR triggering within which the intensity of the PI3K/Akt signal controls entry into either effector or regulatory pathways.
format	article
author	Eloho Etemire Marco Krull Mike Hasenberg Peter Reichardt Matthias Gunzer
author_facet	Eloho Etemire Marco Krull Mike Hasenberg Peter Reichardt Matthias Gunzer
author_sort	Eloho Etemire
title	Transiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.
title_short	Transiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.
title_full	Transiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.
title_fullStr	Transiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.
title_full_unstemmed	Transiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.
title_sort	transiently reduced pi3k/akt activity drives the development of regulatory function in antigen-stimulated naïve t-cells.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/fa839ddb567e4b34a08d2d6690bfdd3a
work_keys_str_mv	AT elohoetemire transientlyreducedpi3kaktactivitydrivesthedevelopmentofregulatoryfunctioninantigenstimulatednaivetcells AT marcokrull transientlyreducedpi3kaktactivitydrivesthedevelopmentofregulatoryfunctioninantigenstimulatednaivetcells AT mikehasenberg transientlyreducedpi3kaktactivitydrivesthedevelopmentofregulatoryfunctioninantigenstimulatednaivetcells AT peterreichardt transientlyreducedpi3kaktactivitydrivesthedevelopmentofregulatoryfunctioninantigenstimulatednaivetcells AT matthiasgunzer transientlyreducedpi3kaktactivitydrivesthedevelopmentofregulatoryfunctioninantigenstimulatednaivetcells
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Transiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.

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