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

Abstract

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

Nrf2 expression driven by Foxp3 specific deletion of Keap1 results in loss of immune tolerance in mice

“…Chapman et al. showed that mTOR signaling is necessary for Treg cell activation and tissue Treg homeostasis by means of a genetic Treg‐specific deletion of mTOR . In contrast, Battaglia et al.…”

“…The role of mTOR signaling in immune tolerance and the possibility of targeting metabolic pathways in order to restore immune tolerance are matters of intensive current research. Chapman et al showed that mTOR signaling is necessary for Treg cell activation and tissue Treg homeostasis by means of a genetic Tregspecific deletion of mTOR [21]. In contrast, Battaglia et al showed that rapamycin selectively expands Tregs [22] and Delgoffe et al showed that mTOR deficient T cells differentiate toward Treg cells [19].…”

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

“…106,107 Interestingly, phosphoproteomic analysis reveals that TCR-induced CAD phosphorylation is mTORC1-dependent, suggesting that mTORC1 also regulates pyrimidine synthesis in T cells. 101 mTORC1-dependent immune responses are also dictated by mitochondrial function, 101,115 which is induced in T cells downstream of mTORC1 by unknown mechanisms. The Rag complex-dependent activation of mTORC1 signaling has a more important role in regulating lysosomal and mitochondrial homeostasis than does the RHEB axis, which partially explains the upstream signaling inputs required for mTORC1-dependent mitochondrial reprogramming in T cells; however, both the Rag complex and RHEB are essential for regulating glycolytic and mitochondrial oxidative phosphorylation in Treg cells.…”

Immune cell metabolism in autoimmunity

“…Activation of both complexes Clinical and Experimental Immunology R E V I E W A RT I C L E Series Editors: Sarah Dimeloe and Claudio Mauro promote glucose metabolism, linking mTORC and glycolysis. T regspecific deletion of mTOR reduced their frequency, leading to spontaneous effector T cell activation and inflammation [18]. mTOR activation promotes the differentiation of T helper type 1 (Th1), Th17 [14] and Tfh T cells [13], three effector subsets that are expanded in lupus [15,16].…”

“…mTOR activation plays a more complex role in regulatory T cell (T reg ) differentiation and function by preventing the generation of long-lived central T regs , but promoting the generation of effector T regs [17]. T regspecific deletion of mTOR reduced their frequency, leading to spontaneous effector T cell activation and inflammation [18]. Deletion of Lkb1 in T regs , the upstream kinase of AMPK and a well-known sensor of metabolic stress, resulted in dysfunctional T regs and the development of a Th2dominant severe autoimmune phenotype [19,20].…”