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

Nicole M. Chapman, Hu Zeng, Thanh-Long M. Nguyen, Yanyan Wang, Peter Vogel, Yogesh Dhungana, Xiaojing Liu, Geoffrey Neale, Jason W. Locasale and Hongbo Chi ()
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Nicole M. Chapman: St. Jude Children’s Research Hospital
Hu Zeng: St. Jude Children’s Research Hospital
Thanh-Long M. Nguyen: St. Jude Children’s Research Hospital
Yanyan Wang: St. Jude Children’s Research Hospital
Peter Vogel: St. Jude Children’s Research Hospital
Yogesh Dhungana: St. Jude Children’s Research Hospital
Xiaojing Liu: Duke University School of Medicine, Levine Science Research Center C266, Box 3813
Geoffrey Neale: St. Jude Children’s Research Hospital
Jason W. Locasale: Duke University School of Medicine, Levine Science Research Center C266, Box 3813
Hongbo Chi: St. Jude Children’s Research Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04392-5

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