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Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming

Author

Listed:
  • Hao Wu

    (Julius-Maximilians University of Würzburg)

  • Xiufeng Zhao

    (Julius-Maximilians University of Würzburg)

  • Sophia M. Hochrein

    (Julius-Maximilians University of Würzburg)

  • Miriam Eckstein

    (Julius-Maximilians University of Würzburg)

  • Gabriela F. Gubert

    (Julius-Maximilians University of Würzburg)

  • Konrad Knöpper

    (Julius-Maximilians University of Würzburg)

  • Ana Maria Mansilla

    (Julius-Maximilians University of Würzburg)

  • Arman Öner

    (University Hospital)

  • Remi Doucet-Ladevèze

    (Julius-Maximilians University of Würzburg)

  • Werner Schmitz

    (Julius-Maximilians University of Würzburg)

  • Bart Ghesquière

    (Center for Cancer Biology, VIB)

  • Sebastian Theurich

    (Cancer and Immunometabolism Research Group
    partner site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU)

  • Jan Dudek

    (Julius-Maximilians University of Würzburg)

  • Georg Gasteiger

    (Julius-Maximilians University of Würzburg)

  • Alma Zernecke

    (University Hospital Würzburg)

  • Sebastian Kobold

    (University Hospital
    partner site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU)

  • Wolfgang Kastenmüller

    (Julius-Maximilians University of Würzburg)

  • Martin Vaeth

    (Julius-Maximilians University of Würzburg)

Abstract

T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.

Suggested Citation

  • Hao Wu & Xiufeng Zhao & Sophia M. Hochrein & Miriam Eckstein & Gabriela F. Gubert & Konrad Knöpper & Ana Maria Mansilla & Arman Öner & Remi Doucet-Ladevèze & Werner Schmitz & Bart Ghesquière & Sebasti, 2023. "Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42634-3
    DOI: 10.1038/s41467-023-42634-3
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    References listed on IDEAS

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