TNF receptor superfamily costimulation couples TCR signal strength to thymic Treg differentiation (BA13P.128)

Regulatory T cells express several TNF receptor superfamily (TNFRSF) members, but their role in thymic Treg development is undefined. We demonstrate that Treg progenitors express high levels of the TNFRSF members GITR, OX40, and TNFR2. Expression of these receptors requires TAK1 and CD28 and correlates directly with TCR signal strength. Neutralizing TNFSF ligands markedly reduced Treg development. Conversely, TNFRSF agonists enhanced Treg differentiation by augmenting IL2R/STAT5 responsiveness. Importantly, GITR-L led to a dose-dependent enrichment of lower-affinity cells within the Treg repertoire. In vivo, GITR- or OX40-deficiency modestly attenuated Treg development; in contrast, combined inhibition of GITR, OX40 and TNFR2 abrogated Treg development. Thus TNFRSF expression on Treg progenitors translates strong TCR signals into molecular parameters that specifically promote Treg differentiation and shape the Treg repertoire.