T-cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. A team led by Martin Vaeth, PhD, at the Institute for Systems Immunology at Julius-Maximilians-Universität (JMU) Würzburg, reports it is now certain that the exhaustion process is significantly influenced by the “powerhouses of the cells”—the mitochondria.

Their findings are published in Nature Communications in an article titled, “Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.”

“Our experiments demonstrate that augmented mitochondrial metabolism also increases the longevity and functionality of virus-specific T cells in chronic infections,” said Vaeth. It is plausible that this strategy can be also harnessed to enhance T-cell-based immunotherapies for cancer therapy.

“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.

“This HIF-1-alpha-dependent control of T-cell exhaustion was previously unknown. It represents a critical regulatory circuit between mitochondrial respiration and T cell function, serving as a ‘metabolic checkpoint’ in the process of T-cell exhaustion,” explained Vaeth.

Looking toward the future, the team wants to explore how mitochondrial respiration influences the epigenetic programming of T cells and the interplay of T-cell metabolism with the local tissue microenvironment.

According to Vaeth, this is particularly important because the nutrient supply and oxygen tension in tumors differ considerably from healthy tissue and T cells must actively respond to this challenging environment.

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