mTOR coordinates transcriptional programs and mitochondrial metabolism of activated T_reg subsets to protect tissue homeostasis.

Regulatory T (T_reg) cells derived from the thymus (tT_reg) and periphery (pT_reg) have central and distinct functions in immunosuppression, but mechanisms for the generation and activation of T_reg subsets in vivo are unclear. Here, we show that mechanistic target of rapamycin (mTOR) unexpectedly supports the homeostasis and functional activation of tT_reg and pT_reg cells. mTOR signaling is crucial for programming activated T_reg-cell function to protect immune tolerance and tissue homeostasis. T_reg-specific deletion of mTOR drives spontaneous effector T-cell activation and inflammation in barrier tissues and is associated with reduction in both thymic-derived effector T_reg (eT_reg) and pT_reg cells. Mechanistically, mTOR functions downstream of antigenic signals to drive IRF4 expression and mitochondrial metabolism, and accordingly, deletion of mitochondrial transcription factor A (Tfam) severely impairs T_reg-cell suppressive function and eT_reg-cell generation. Collectively, our results show that mTOR coordinates transcriptional and metabolic programs in activated T_reg subsets to mediate tissue homeostasis.