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PPAR-γ regulates the effector function of human T helper 9 cells by promoting glycolysis

Author

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  • Nicole L. Bertschi

    (Bern University Hospital, University of Bern)

  • Oliver Steck

    (Bern University Hospital, University of Bern)

  • Fabian Luther

    (Bern University Hospital, University of Bern)

  • Cecilia Bazzini

    (Bern University Hospital, University of Bern)

  • Leonhard Meyenn

    (Bern University Hospital, University of Bern)

  • Stefanie Schärli

    (Bern University Hospital, University of Bern)

  • Angela Vallone

    (Bern University Hospital, University of Bern)

  • Andrea Felser

    (University of Bern)

  • Irene Keller

    (University of Bern)

  • Olivier Friedli

    (University of Bern)

  • Stefan Freigang

    (University of Bern)

  • Nadja Begré

    (Bern University Hospital, University of Bern)

  • Susanne Radonjic-Hoesli

    (Bern University Hospital, University of Bern)

  • Cristina Lamos

    (Bern University Hospital, University of Bern)

  • Max Philip Gabutti

    (Bern University Hospital, University of Bern)

  • Michael Benzaquen

    (Bern University Hospital, University of Bern)

  • Markus Laimer

    (Bern University Hospital, University of Bern)

  • Dagmar Simon

    (Bern University Hospital, University of Bern)

  • Jean-Marc Nuoffer

    (University of Bern)

  • Christoph Schlapbach

    (Bern University Hospital, University of Bern)

Abstract

T helper 9 (TH9) cells promote allergic tissue inflammation and express the type 2 cytokines, IL-9 and IL-13, as well as the transcription factor, PPAR-γ. However, the functional role of PPAR-γ in human TH9 cells remains unknown. Here, we demonstrate that PPAR-γ drives activation-induced glycolysis, which, in turn, promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments show that the PPAR-γ-mTORC1-IL-9 pathway is active in TH9 cells in human skin inflammation. Additionally, we find dynamic regulation of tissue glucose levels in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological functions in vivo. Furthermore, paracrine IL-9 induces expression of the lactate transporter, MCT1, in TH cells and promotes their aerobic glycolysis and proliferative capacity. Altogether, our findings uncover a hitherto unknown relationship between PPAR-γ-dependent glucose metabolism and pathogenic effector functions in human TH9 cells.

Suggested Citation

  • Nicole L. Bertschi & Oliver Steck & Fabian Luther & Cecilia Bazzini & Leonhard Meyenn & Stefanie Schärli & Angela Vallone & Andrea Felser & Irene Keller & Olivier Friedli & Stefan Freigang & Nadja Beg, 2023. "PPAR-γ regulates the effector function of human T helper 9 cells by promoting glycolysis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38233-x
    DOI: 10.1038/s41467-023-38233-x
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    References listed on IDEAS

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    1. Youdong Pan & Tian Tian & Chang Ook Park & Serena Y. Lofftus & Shenglin Mei & Xing Liu & Chi Luo & John T. O’Malley & Ahmed Gehad & Jessica E. Teague & Sherrie J. Divito & Robert Fuhlbrigge & Pere Pui, 2017. "Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism," Nature, Nature, vol. 543(7644), pages 252-256, March.
    2. Lintao Liu & Enguang Bi & Xingzhe Ma & Wei Xiong & Jianfei Qian & Lingqun Ye & Pan Su & Qiang Wang & Liuling Xiao & Maojie Yang & Yong Lu & Qing Yi, 2020. "Enhanced CAR-T activity against established tumors by polarizing human T cells to secrete interleukin-9," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    3. Mulki Angela & Yusuke Endo & Hikari K. Asou & Takeshi Yamamoto & Damon J. Tumes & Hirotake Tokuyama & Koutaro Yokote & Toshinori Nakayama, 2016. "Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells," Nature Communications, Nature, vol. 7(1), pages 1-15, December.
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