| First Author | Wu H | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 6858 |
| PubMed ID | 37891230 | Mgi Jnum | J:354470 |
| Mgi Id | MGI:7546357 | Doi | 10.1038/s41467-023-42634-3 |
| Citation | Wu H, et al. (2023) Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1alpha-mediated glycolytic reprogramming. Nat Commun 14(1):6858 |
| abstractText | 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 1alpha (HIF-1alpha) 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. |
