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Wu, Hao; Zhao, Xiufeng; Hochrein, Sophia M; Eckstein, Miriam; Gubert, Gabriela F; Knöpper, Konrad; Mansilla, Ana Maria; Öner, Arman; Doucet-Ladevèze, Remi; Schmitz, Werner; Ghesquière, Bart; Theurich, Sebastian; Dudek, Jan; Gasteiger, Georg; Zernecke, Alma; Kobold, Sebastian; Kastenmüller, Wolfgang; Vaeth, Martin
Nature communications, 10/2023, Volume: 14, Issue: 1Journal Article
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.
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