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

Nature Communications
Nicole M ChapmanHongbo Chi

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.

References

Jan 11, 2003·Science·Shohei HoriShimon Sakaguchi
Mar 4, 2003·Nature Immunology·Jason D FontenotAlexander Y Rudensky
Mar 5, 2005·Blood·Manuela BattagliaMaria-Grazia Roncarolo
Nov 4, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Dulce SolerRoland Kolbeck
Dec 1, 2006·Nature Immunology·Jeong M KimAlexander Y Rudensky
Mar 3, 2009·Nature Immunology·R Lee ReinhardtRichard M Locksley
Feb 26, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Angela M ThorntonEthan M Shevach
Jul 16, 2010·Bioinformatics·Jianguo Xia, David S Wishart
Dec 15, 2010·Immunity·Claudio ProcacciniGiuseppe Matarese
Feb 15, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ryan D MichalekJeffrey C Rathmell
Jul 26, 2011·Nature Medicine·Michelle A LintermanCarola G Vinuesa
Oct 4, 2011·The Journal of Clinical Investigation·Elizabeth A WohlfertYasmine Belkaid
Oct 11, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ivonne WollenbergLuis Graca
Feb 10, 2012·Nature·Steven Z JosefowiczAlexander Y Rudensky
Aug 28, 2012·Nature Immunology·Dipayan RudraAlexander Y Rudensky
Sep 12, 2012·The Journal of Experimental Medicine·Mahesh YadavJeffrey A Bluestone
Mar 20, 2013·Nature Immunology·Abul K AbbasSteve F Ziegler
Mar 26, 2013·Immunity·Naganari OhkuraShimon Sakaguchi
Nov 26, 2013·The Journal of Clinical Investigation·Yoon ParkYun-Cai Liu
Jan 1, 2014·The Journal of Experimental Medicine·Kate S SmigielDaniel J Campbell
Jan 15, 2014·Analytical Chemistry·Xiaojing LiuJason W Locasale
Jul 22, 2014·Nature·Chris SchieringFiona Powrie
Sep 30, 2014·Nature Immunology·Andrew G LevineAlexander Y Rudensky
Dec 2, 2014·The Journal of Clinical Investigation·Valerie A GerrietsJeffrey C Rathmell
Dec 4, 2014·Immunity·J Christoph VahlMarc Schmidt-Supprian
Jan 7, 2015·Nature Immunology·Alexandria HuynhLaurence A Turka
Jan 7, 2015·Nature Immunology·Sharad ShresthaHongbo Chi
Aug 25, 2015·Cell Metabolism·Francesc BaixauliMaria Mittelbrunn
Oct 10, 2015·Nucleic Acids Research·Sarah E CalvoVamsi K Mootha
Jan 9, 2016·Nature Communications·KyeongJin KimUtpal B Pajvani

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Citations

Feb 17, 2019·Clinical and Experimental Immunology·X TengL Morel
Mar 13, 2020·Immunological Reviews·Xiangyu TengLaurence Morel
May 10, 2020·The FEBS Journal·Liesa S ZieglerKlaus G Schmetterer
May 6, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Rianne OpsteltenDerk Amsen
May 23, 2020·Science·Gabriela Desdín-MicóMaría Mittelbrunn
Aug 26, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Romain VallionBenoit L Salomon
May 21, 2019·Expert Review of Clinical Immunology·Monika Ryba-StanisławowskaPiotr Trzonkowski
Jan 11, 2020·Frontiers in Immunology·Hao Shi, Hongbo Chi
Oct 16, 2018·Frontiers in Cell and Developmental Biology·Robert J Salmond
Jan 4, 2019·Nature Cell Biology·Jonathan JungTiffany Horng
Mar 14, 2019·Nature Communications·Martin VaethStefan Feske
Mar 15, 2019·Cellular & Molecular Immunology·Jordy SaraviaHongbo Chi
Dec 19, 2019·Frontiers in Immunology·Rosalie W M KempkesXuehui He
Dec 20, 2019·JCI Insight·Margaret M LoweMichael D Rosenblum
Jan 9, 2020·Science Advances·Jordy SaraviaHongbo Chi
Mar 24, 2020·Cell Research·Jordy SaraviaHongbo Chi
May 1, 2020·Cellular and Molecular Life Sciences : CMLS·Ke Wang, Wenxian Fu
Oct 6, 2020·Frontiers in Immunology·Mo AtifMakoto Miyara
Mar 27, 2020·Immunological Reviews·Hongling HuangHongbo Chi
Aug 15, 2020·Frontiers in Immunology·Rebecca A Brown, Craig A Byersdorfer
Aug 14, 2019·Nature Reviews. Immunology·Nicole M ChapmanHongbo Chi
Oct 18, 2020·European Journal of Immunology·Henry KurniawanDirk Brenner
Feb 4, 2021·Cancer Immunology, Immunotherapy : CII·Varun Sasidharan NairEyad Elkord
Mar 4, 2020·The Journal of Clinical Investigation·Giorgia AlvisiEnrico Lugli
Mar 7, 2021·Current Opinion in Biotechnology·Jun WeiHongbo Chi
Feb 21, 2021·Ageing Research Reviews·Qiong ZhuLingqiang Zhang
Jul 16, 2020·Cell Metabolism·Karthik VasanNavdeep S Chandel
Apr 4, 2021·International Journal of Molecular Sciences·Ryuhjin Ahn, Josie Ursini-Siegel
May 1, 2021·International Journal of Molecular Sciences·Alessandra RossiSilvia Piconese
Apr 22, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Chengxian XuKai Yang
Apr 20, 2021·Frontiers in Immunology·Julianna BlagihFabio Zani
May 18, 2021·Frontiers in Immunology·Cesare TripolinoFrancesco Ursini

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Datasets Mentioned

BETA
GSE61077
7
GSE104130

Methods Mentioned

BETA
PMA
flow cytometry
metabolomics profiling
fluorescence activated cell sorter
PCR
ChIP-seq

Software Mentioned

GSEA
Limma
GraphPad Prism
Bioconductor
MetaboAnalyst
Partek Genomics Suite

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