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

Regulatory T (T) cells derived from the thymus (tT) and periphery (pT) have central and distinct functions in immunosuppression, but mechanisms for the generation and activation of T subsets in vivo are unclear. Here, we show that mechanistic target of rapamycin (mTOR) unexpectedly supports the homeostasis and functional activation of tT and pT cells. mTOR signaling is crucial for programming activated T-cell function to protect immune tolerance and tissue homeostasis. T-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 (eT) and pT 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-cell suppressive function and eT-cell generation. Collectively, our results show that mTOR coordinates transcriptional and metabolic programs in activated T subsets to mediate tissue homeostasis.