Journal
NATURE IMMUNOLOGY
Volume 15, Issue 5, Pages 473-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.2849
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Funding
- University of Minnesota [2T32AI007313]
- University of Minnesota Medical Scientist Training Program [5T32GM008244]
- US National Institutes of Health [F30DK096844, F30DK100159, HL062683, AI101407, NS64599, AI088209, CA154998, CA151845, AI061165]
- US National Cancer Institute [1F31CA183226]
- University of Minnesota Undergraduate Research Opportunities Program (H.M.S.)
- Leukemia and Lymphoma Society (M.A.F.)
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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 Treg 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.
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