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

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, Sebastian Theurich, Jan Dudek, Georg Gasteiger, Alma Zernecke, Sebastian Kobold, Wolfgang Kastenmüller and Martin Vaeth ()
Additional contact information
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
Jan Dudek: Julius-Maximilians University of Würzburg
Georg Gasteiger: Julius-Maximilians University of Würzburg
Alma Zernecke: University Hospital Würzburg
Sebastian Kobold: University Hospital
Wolfgang Kastenmüller: Julius-Maximilians University of Würzburg
Martin Vaeth: Julius-Maximilians University of Würzburg

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42634-3

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