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

Abstract 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 mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition) (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.