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Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4

T cell development requires phosphatidylinositol 3-kinase (PI3K) signaling with contributions from both the class IA, p110δ, and class IB, p110γ catalytic subunits. However, the receptors on immature T cells by which each of these PI3Ks are activated have not been identified, nor has the mechanism b...

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Autores principales: Janas, Michelle L., Varano, Gabriele, Gudmundsson, Kristjan, Noda, Mamiko, Nagasawa, Takashi, Turner, Martin
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812547/
https://www.ncbi.nlm.nih.gov/pubmed/20038597
http://dx.doi.org/10.1084/jem.20091430
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author Janas, Michelle L.
Varano, Gabriele
Gudmundsson, Kristjan
Noda, Mamiko
Nagasawa, Takashi
Turner, Martin
author_facet Janas, Michelle L.
Varano, Gabriele
Gudmundsson, Kristjan
Noda, Mamiko
Nagasawa, Takashi
Turner, Martin
author_sort Janas, Michelle L.
collection PubMed
description T cell development requires phosphatidylinositol 3-kinase (PI3K) signaling with contributions from both the class IA, p110δ, and class IB, p110γ catalytic subunits. However, the receptors on immature T cells by which each of these PI3Ks are activated have not been identified, nor has the mechanism behind their functional redundancy in the thymus. Here, we show that PI3K signaling from the preTCR requires p110δ, but not p110γ. Mice deficient for the class IB regulatory subunit p101 demonstrated the requirement for p101 in T cell development, implicating G protein–coupled receptor signaling in β-selection. We found evidence of a role for CXCR4 using small molecule antagonists in an in vitro model of β-selection and demonstrated a requirement for CXCR4 during thymic development in CXCR4-deficient embryos. Finally, we demonstrate that CXCL12, the ligand for CXCR4, allows for Notch-dependent differentiation of DN3 thymocytes in the absence of supporting stromal cells. These findings establish a role for CXCR4-mediated PI3K signaling that, together with signals from Notch and the preTCR, contributes to continued T cell development beyond β-selection.
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spelling pubmed-28125472010-07-18 Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4 Janas, Michelle L. Varano, Gabriele Gudmundsson, Kristjan Noda, Mamiko Nagasawa, Takashi Turner, Martin J Exp Med Article T cell development requires phosphatidylinositol 3-kinase (PI3K) signaling with contributions from both the class IA, p110δ, and class IB, p110γ catalytic subunits. However, the receptors on immature T cells by which each of these PI3Ks are activated have not been identified, nor has the mechanism behind their functional redundancy in the thymus. Here, we show that PI3K signaling from the preTCR requires p110δ, but not p110γ. Mice deficient for the class IB regulatory subunit p101 demonstrated the requirement for p101 in T cell development, implicating G protein–coupled receptor signaling in β-selection. We found evidence of a role for CXCR4 using small molecule antagonists in an in vitro model of β-selection and demonstrated a requirement for CXCR4 during thymic development in CXCR4-deficient embryos. Finally, we demonstrate that CXCL12, the ligand for CXCR4, allows for Notch-dependent differentiation of DN3 thymocytes in the absence of supporting stromal cells. These findings establish a role for CXCR4-mediated PI3K signaling that, together with signals from Notch and the preTCR, contributes to continued T cell development beyond β-selection. The Rockefeller University Press 2010-01-18 /pmc/articles/PMC2812547/ /pubmed/20038597 http://dx.doi.org/10.1084/jem.20091430 Text en © 2010 Janas 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.jem.org/misc/terms.shtml). 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
Janas, Michelle L.
Varano, Gabriele
Gudmundsson, Kristjan
Noda, Mamiko
Nagasawa, Takashi
Turner, Martin
Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4
title Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4
title_full Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4
title_fullStr Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4
title_full_unstemmed Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4
title_short Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4
title_sort thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by cxcr4
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812547/
https://www.ncbi.nlm.nih.gov/pubmed/20038597
http://dx.doi.org/10.1084/jem.20091430
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