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 language | English |
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Pages (from-to) | 473-481 |
Number of pages | 9 |
Journal | Nature Immunology |
Volume | 15 |
Issue number | 5 |
DOIs | |
State | Published - May 2014 |
Scopus Subject Areas
- Immunology and Allergy
- Immunology