Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells

Shawn A. Mahmud, Luke S. Manlove, Heather M. Schmitz, Yan Xing, Yanyan Wang, David L. Owen, Jason M. Schenkel, Jonathan S. Boomer, Jonathan M. Green, Hideo Yagita, Hongbo Chi, Kristin A. Hogquist, Michael A. Farrar

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

Regulatory T cells (T reg cells) express members of the tumor-necrosis factor (TNF) receptor superfamily (TNFRSF), but the role of those receptors in the thymic development of T reg cells is undefined. We found here that T reg cell progenitors had high expression of the TNFRSF members GITR, OX40 and TNFR2. Expression of those receptors correlated directly with the signal strength of the T cell antigen receptor (TCR) and required the coreceptor CD28 and the kinase TAK1. The neutralization of ligands that are members of the TNF superfamily (TNFSF) diminished the development of T reg cells. Conversely, TNFRSF agonists enhanced the differentiation of T reg cell progenitors by augmenting responsiveness of the interleukin 2 receptor (IL-2R) and transcription factor STAT5. Costimulation with the ligand of GITR elicited dose-dependent enrichment for cells of lower TCR affinity in the T reg cell repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated the development of T reg cells. Thus, expression of members of the TNFRSF on T reg cell progenitors translated strong TCR signals into molecular parameters that specifically promoted the development of T reg cells and shaped the T reg cell repertoire.

Original languageEnglish (US)
Pages (from-to)473-481
Number of pages9
JournalNature immunology
Volume15
Issue number5
DOIs
StatePublished - May 2014

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