TGF-β suppresses RasGRP1 expression and supports regulatory T cell resistance against p53-induced CD28-dependent T-cell apoptosis.

Thymus-derived regulatory T cells (tTregs) play pivotal roles in immunological self-tolerance and homeostasis. A majority of tTregs are reactive to self-antigens and are constantly exposed to antigenic stimulation. Despite this continuous stimulation, tTreg and conventional T-cell populations remain balanced during homeostasis, but the mechanisms controlling this balance are unknown. We previously reported a form of activation-induced cell death, which is dependent on p53 (p53-induced CD28-dependent T-cell apoptosis, PICA). Under PICA-inducing conditions, tTregs survive while a majority of conventional T cells undergo apoptosis, suggesting there is a survival mechanism that protects tTregs. Here, we report that the expression of RasGRP1 (Ras guanyl-releasing protein 1) is required for PICA, as conventional T cells isolated from RasGRP1-deficient mice become resistant to PICA. After continuous stimulation, tTregs express a substantially lower amount of RasGRP1 compared to conventional T cells. This reduced expression of RasGRP1 is dependent on TGF-β, as addition of TGF-β to conventional T cells reduces RasGRP1 expression. Conversely, RasGRP1 expression in tTregs increases when TGF-β signaling is inhibited. Together, these data show that RasGRP1 expression is repressed in tTregs by TGF-β signaling and suggests that reduced RasGRP1 expression is critical for tTregs to resist apoptosis caused by continuous antigen exposure.