Mito dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming, 2023, Hau Wu

A team led by researchers at the Institute for Systems Immunology at JMU of Würzburg has demonstrated it is now certain that the mitochondria significantly influence the exhaustion process

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.

https://www.nature.com/articles/s41467-023-42634-3

 

“It was commonly assumed that the observed alterations in the mitochondrial (energy) metabolism were a consequence of T-cell exhaustion,” said Vaeth. To demonstrate that mitochondrial dysfunction is the actual cause of T-cell exhaustion, his team developed a new genetic model. It switches off the mitochondrial phosphate transporter (SLC25A3) and paralyses mitochondrial respiration in T cells.

T cells are forced to switch to alternative metabolic pathways, mainly aerobic glycolysis, to meet their bioenergetic demand in the form of adenosine triphosphate. However, this metabolic adaptation causes an increased production of reactive oxygen species in the T cells.

https://www.medicalnewstoday.com/articles/318750#causes