TCR–mTORC1 signaling promotes epigenetic stabilization of Foxp3 expression in regulatory T cells via TET protein translation

Regulatory T (Treg) cell differentiation and function rely on stable expression of the master transcription factor Foxp3. While Foxp3 expression is epigenetically stabilized through DNA demethylation of a Foxp3 enhancer (the Treg-specific demethylated region, TSDR), the mechanisms underlying this process remain unclear. Here, we show that strong and sustained T cell receptor (TCR) signaling promotes TSDR demethylation, stabilizes Foxp3 expression, and confers suppressive activity in in vitro–induced Treg (iTreg) cells through activation of mTORC1. Mechanistically, TCR–mTORC1 signaling promotes TSDR demethylation by enhancing translation of TET2, and likely TET3, enzymes that mediate DNA demethylation. Rescue of impaired TSDR demethylation under mTORC1 inhibition by the TET2 catalytic domain, together with dose-dependent impairment following heterozygous deficiency of TET2 and/or TET3, supports a causal link between TET protein abundance and TSDR demethylation. In vivo, mTORC1 inactivation increases the frequency of cells harboring a methylated TSDR among peripheral Foxp3 + T cells, but not among developing Foxp3 + thymocytes, supporting in vivo relevance of mTORC1-dependent epigenetic remodeling. Thus, TCR–mTORC1 signaling promotes epigenetic stabilization of Foxp3 expression through translational control of TET proteins, revealing an unrecognized role for mTORC1 in iTreg cell differentiation.