Würzburg Institute of Systems Immunology, Max Planck Research Group, Julius-Maximilians University of Würzburg, Würzburg, Germany.
Division of Clinical Pharmacology, Department of Medicine IV, Ludwig Maximilians University (LMU) Munich, University Hospital, Munich, Germany.
Nat Commun. 2023 Oct 27;14(1):6858. doi: 10.1038/s41467-023-42634-3.
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.
T 细胞耗竭是癌症和持续性感染的标志，其特征是抑制性受体上调、细胞因子分泌减少和细胞溶解活性受损。终末耗竭的 T 细胞可被前体细胞群（Tpex）不断补充，但控制 Tpex 维持的代谢原则和控制其耗竭的调节回路仍不完全清楚。我们使用基因缺陷小鼠、单细胞转录组学和代谢组学分析的组合，表明线粒体功能不全是引发 T 细胞功能耗竭的细胞内触发因素。在分子水平上，我们发现线粒体功能障碍导致氧化应激，从而抑制缺氧诱导因子 1α（HIF-1α）的蛋白酶体降解，并促进 Tpex 细胞向终末耗竭 T 细胞的转录和代谢重编程。我们的研究结果还具有临床意义，因为嵌合抗原受体（CAR）T 细胞的代谢工程是增强 Tpex 细胞用于癌症免疫治疗的干性和功能的有前途的策略。
