TY  - JOUR
A1  - Wu, Hao
A1  - Zhao, Xiufeng
A1  - Hochrein, Sophia M.
A1  - Eckstein, Miriam
A1  - Gubert, Gabriela F.
A1  - Knöpper, Konrad
A1  - Mansilla, Ana Maria
A1  - Öner, Arman
A1  - Doucet-Ladevèze, Remi
A1  - Schmitz, Werner
A1  - Ghesquière, Bart
A1  - Theurich, Sebastian
A1  - Dudek, Jan
A1  - Gasteiger, Georg
A1  - Zernecke, Alma
A1  - Kobold, Sebastian
A1  - Kastenmüller, Wolfgang
A1  - Vaeth, Martin
T1  - Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming
JF  - Nature Communications
N2  - 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.
KW  - cytotoxic T cells
KW  - infection
KW  - lymphocyte differentiation
KW  - translational research
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358052
VL  - 14
ER  -