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.
Bibliographical noteFunding Information:
We thank C. Riccardi (Universita Di Perugia) and E. Shevach (US National Institutes of Health) for Gitr−/− mice; R. Schreiber (Washington University) for neutralizing antibody to TNFR2; G. Hubbard, A. Kne and C. Reis for assistance with animal husbandry; T. Martin, J. Motl and P. Champoux for cell sorting and maintenance of the Flow Cytometry Core Facility at the University of Minnesota (5P01AI035296); and C. Katerndahl, A. Moran, A. Pagán, G. Stritesky, K. Pauken, L. Heltemes-Harris and K. Berquam-Vrieze for comments and for reviewing the manuscript. Supported by the Immunology Training Program of the University of Minnesota (2T32AI007313 to S.A.M. and J.M.S.), the University of Minnesota Medical Scientist Training Program (5T32GM008244 to S.A.M. and J.M.S.), the US National Institutes of Health (F30DK096844 and F30DK100159 to S.A.M. and J.M.S.; HL062683 to J.S.B. and J.M.G.; AI101407 and NS64599 to H.C. and Y.W.; AI088209 to K.A.H. and Y.X.; and CA154998, CA151845 and AI061165 to M.A.F.), the US National Cancer Institute (1F31CA183226 to L.S.M.), the University of Minnesota Undergraduate Research Opportunities Program (H.M.S.) and the Leukemia and Lymphoma Society (M.A.F.).