HIF-1a-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cells
WU H. 1, ZHAO X. 1, ÖNER A. 2, HOCHREIN . 1, ECKSTEIN M. 1, KNÖPPER K. 1, MANSILLA A. 1, DOUCET-LADEVÈZE R. 1, GHESQUIÈRE B. 3, THEURICH S. 4, DUDEK J. 5, GASTEIGER G. 1, ZERNECKE-MADSEN A. 6, KOBOLD S. 2,7, KASTENMÜLLER W. 1, VAETH M. 1
1 Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians University of Würzburg, Würzburg, Germany, Wuerzburg, Germany; 2 Center for Integrated Protein Science Munich (CIPSM) and Division of Clinical Pharmacology, Department of Medicine IV, Ludwig Maximilians University (LMU) Munich, University Hospital, Munich, Germany. Member of the German Center for Lung Research (DZL)., Munich, Germany; 3 Metabolomics Expertise Center, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium, Leuven, Belgium; 4 Ludwig Maximilians University (LMU) Munich, University Hospital, Department of Medicine III, Munich, Germany and LMU Gene Center, Cancer and Immunometabolism Research Group, Munich, Germany, Munich, Germany; 5 Comprehensive Heart Failure Center (CHFC), University Hospital, Julius-Maximilians University of Würzburg, Würzburg, Germany., Würzburg, Germany; 6 Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany, Würzburg, Germany; 7 German Center for Translational Cancer Research (DKTK), partner site Munich, Munich, Germany
The functional exhaustion of T cells in cancer and persistent infections is characterized by the upregulation of inhibitory receptors, the progressive decline in cytokine secretion and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex) with phenotypic features of memory T cells and a stem-like capacity to selfrenew. However, the metabolic principles of Tpex maintenance and the regulatory circuits that control the exhaustion of their progeny remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics and metabolomic analyses, we here show that mitochondrial dysfunction is a cell-intrinsic trigger that initiates the T cell exhaustion program. At the molecular level, we found that diminished mitochondrial respiration and metabolic remodeling cause oxidative stress, which inhibits the proteasomal degradation of hypoxia inducible factor 1 alpha (HIF-1a) in Tpex cells. HIF-1a-mediated gene expression promotes the glycolytic reprogramming of Tpex cells as an initial step towards terminal differentiation and dysfunction. Finally, we show that glycolytic restriction of CAR T cells is a promising metabolic intervention strategy to preserve the stemness of Tpex cells during chronic viral infection and cancer immunotherapy.