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.
Highlights
Regulatory T (Treg) cells derived from the thymus and periphery have central and distinct functions in immunosuppression, but mechanisms for the generation and activation of Treg subsets in vivo are unclear
To identify pathways associated with increased suppressive function of Treg cells, we mined a published dataset of activated Treg cells isolated from diphtheria toxin (DT)-treated Foxp3DTR mice (DTR, diphtheria toxin receptor)[32]
Activated Thymic-derived Treg (tTreg) and pTreg cells are crucial for peripheral T-cell tolerance and tissue homeostasis
Summary
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. MTOR signaling is crucial for programming activated Treg-cell function to protect immune tolerance and tissue homeostasis. MTOR functions downstream of antigenic signals to drive IRF4 expression and mitochondrial metabolism, and deletion of mitochondrial transcription factor A (Tfam) severely impairs Treg-cell suppressive function and eTreg-cell generation. Our results show that mTOR coordinates transcriptional and metabolic programs in activated Treg subsets to mediate tissue homeostasis. Regulatory T (Treg) cells expressing the transcription factor Foxp[3] suppress conventional T-cell responses to establish self-tolerance, prevent autoimmunity, and maintain tissue homeostasis[1,2]. Thymic-derived Treg (tTreg) cells exit the helper (TFH) thymus and populate peripheral tissues, where resting Treg cells [ called cineflnatrmalmTarteogr(ycTcrueeg)s6c–e9l.lsT] haereseacatcitviavtaetdioinn response to antigen and signals increase effector molecule expression and induce transcription factors that define the selective suppressive functions and tissue localization of acecltlisv]a5t,1e0d–15T. MTOR-dependent metabolic programming might have context-dependent roles in different Treg-subsets or under distinct physiological conditions
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