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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Nicole M. Chapman & Hu Zeng & Thanh-Long M. Nguyen & Yanyan Wang & Peter Vogel & Yogesh Dhungana & Xiaojing Liu & Geoffrey Neale & Jason W. Locasale & Hongbo Chi, 2018. "mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04392-5
    DOI: 10.1038/s41467-018-04392-5
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