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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Detalles Bibliográficos
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
Descripción
Sumario: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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