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

著者: Nicole M. Chapman, Hu Zeng, Thanh-Long M. Nguyen, Yanyan Wang, Peter Vogel, Yogesh Dhungana, Xiaojing Liu, Geoffrey Neale, Jason W. Locasale, Hongbo Chi - Nature Communications 2018 被引用: 193

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 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.