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

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.