Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation

Regulatory T (T(reg)) cells express tumor necrosis factor receptor superfamily (TNFRSF) members, but their role in thymic T(reg) development is undefined. We demonstrate that T(reg) progenitors highly express the TNFRSF members GITR, OX40, and TNFR2. Expression of these receptors correlates directly...

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Autores principales: Mahmud, Shawn A., Manlove, Luke S., Schmitz, Heather M., Xing, Yan, Wang, Yanyan, Owen, David L., Schenkel, Jason M., Boomer, Jonathan S., Green, Jonathan M., Yagita, Hideo, Chi, Hongbo, Hogquist, Kristin A., Farrar, Michael A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000541/
https://www.ncbi.nlm.nih.gov/pubmed/24633226
http://dx.doi.org/10.1038/ni.2849
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author Mahmud, Shawn A.
Manlove, Luke S.
Schmitz, Heather M.
Xing, Yan
Wang, Yanyan
Owen, David L.
Schenkel, Jason M.
Boomer, Jonathan S.
Green, Jonathan M.
Yagita, Hideo
Chi, Hongbo
Hogquist, Kristin A.
Farrar, Michael A.
author_facet Mahmud, Shawn A.
Manlove, Luke S.
Schmitz, Heather M.
Xing, Yan
Wang, Yanyan
Owen, David L.
Schenkel, Jason M.
Boomer, Jonathan S.
Green, Jonathan M.
Yagita, Hideo
Chi, Hongbo
Hogquist, Kristin A.
Farrar, Michael A.
author_sort Mahmud, Shawn A.
collection PubMed
description Regulatory T (T(reg)) cells express tumor necrosis factor receptor superfamily (TNFRSF) members, but their role in thymic T(reg) development is undefined. We demonstrate that T(reg) progenitors highly express the TNFRSF members GITR, OX40, and TNFR2. Expression of these receptors correlates directly with T cell receptor (TCR) signal strength, and requires CD28 and the kinase TAK1. Neutralizing TNFSF ligands markedly reduced T(reg) development. Conversely, TNFRSF agonists enhanced T(reg) differentiation by augmenting IL-2R/STAT5 responsiveness. GITR-ligand costimulation elicited a dose-dependent enrichment of lower-affinity cells within the T(reg) repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated T(reg) development. Thus TNFRSF expression on T(reg) progenitors translates strong TCR signals into molecular parameters that specifically promote T(reg) differentiation and shape the T(reg) repertoire.
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spelling pubmed-40005412014-11-01 Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation Mahmud, Shawn A. Manlove, Luke S. Schmitz, Heather M. Xing, Yan Wang, Yanyan Owen, David L. Schenkel, Jason M. Boomer, Jonathan S. Green, Jonathan M. Yagita, Hideo Chi, Hongbo Hogquist, Kristin A. Farrar, Michael A. Nat Immunol Article Regulatory T (T(reg)) cells express tumor necrosis factor receptor superfamily (TNFRSF) members, but their role in thymic T(reg) development is undefined. We demonstrate that T(reg) progenitors highly express the TNFRSF members GITR, OX40, and TNFR2. Expression of these receptors correlates directly with T cell receptor (TCR) signal strength, and requires CD28 and the kinase TAK1. Neutralizing TNFSF ligands markedly reduced T(reg) development. Conversely, TNFRSF agonists enhanced T(reg) differentiation by augmenting IL-2R/STAT5 responsiveness. GITR-ligand costimulation elicited a dose-dependent enrichment of lower-affinity cells within the T(reg) repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated T(reg) development. Thus TNFRSF expression on T(reg) progenitors translates strong TCR signals into molecular parameters that specifically promote T(reg) differentiation and shape the T(reg) repertoire. 2014-03-16 2014-05 /pmc/articles/PMC4000541/ /pubmed/24633226 http://dx.doi.org/10.1038/ni.2849 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
Mahmud, Shawn A.
Manlove, Luke S.
Schmitz, Heather M.
Xing, Yan
Wang, Yanyan
Owen, David L.
Schenkel, Jason M.
Boomer, Jonathan S.
Green, Jonathan M.
Yagita, Hideo
Chi, Hongbo
Hogquist, Kristin A.
Farrar, Michael A.
Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation
title Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation
title_full Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation
title_fullStr Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation
title_full_unstemmed Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation
title_short Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation
title_sort tumor necrosis factor receptor superfamily costimulation couples t cell receptor signal strength to thymic regulatory t cell differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000541/
https://www.ncbi.nlm.nih.gov/pubmed/24633226
http://dx.doi.org/10.1038/ni.2849
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