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Nat Commun. 2018 May 29;9(1):2095. doi: 10.1038/s41467-018-04392-5.

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

Author information

1
Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 351, Memphis, TN, 38105, USA.
2
Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 250, Memphis, TN, 38105, USA.
3
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Levine Science Research Center C266, Box 3813, Durham, NC, 27710, USA.
4
Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 312, Memphis, TN, 38105, USA.
5
Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 351, Memphis, TN, 38105, USA. hongbo.chi@stjude.org.

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.

PMID:
29844370
PMCID:
PMC5974344
DOI:
10.1038/s41467-018-04392-5
[Indexed for MEDLINE]
Free PMC Article

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