Mitochondrial Dysfunction is a Contributing Cause of T Cell Exhaustion
T cell exhaustion occurs in aging, but also in circumstances in which the adaptive immune system is constantly stimulated over time, such as in cases of persistent HIV infection, or the presence of solid tumors. An exhausted T cell has adopted a state in which it is functionally incapable, no longer responsive to antigens. Ways to reverse T cell exhaustion would be very beneficial, and so the research community has made some inroads in understanding the mechanisms of exhaustion, enough to produce proof of concept approaches, such as those involving epigenetic reprogramming, BAFT upregulation, TIGIT knockdown, and various small molecules identified in screening programs.
In today's research materials, scientists provide evidence for T cell exhaustion to be caused by mitochondrial dysfunction. Thus ways to maintain or restore mitochondrial function will allow cells to resist the exhausted state. This may explain the success that researchers have had with epigenetic reprogramming in the context of T cell exhaustion, as this intervention is well known to restore mitochondrial function. Overall, this finding is quite interesting in the context of age-related T cell exhaustion, given the mitochondrial dysfunction that occurs with advancing age. It suggests that all strategies that can improve mitochondrial function may produce corresponding gains in immune function.
Preventing the Exhaustion of T Cells
When mitochondrial respiration fails, a cascade of reactions is triggered, culminating in the genetic and metabolic reprogramming of T cells - a process that drives their functional exhaustion. But this "burnout" of the T cells can be counteracted: pharmacological or genetic optimization of cellular metabolism increases the longevity and functionality of T cells. This can be achieved, for example, by overexpressing a mitochondrial phosphate transporter that drives the production of the energy-providing molecule adenosine-triphosphate.
"It was commonly assumed that the observed alterations in the mitochondrial metabolism were a consequence of T-cell exhaustion." To demonstrate that mitochondrial dysfunction is the actual cause of T cell exhaustion, researcher developed a new genetic model. It switches off the mitochondrial phosphate transporter (SLC25A3) and paralyses mitochondrial respiration in T cells. As a result, the 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.
Elevated levels of oxygen radicals prevent the degradation of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1-alpha). The accumulation of HIF-1-alpha protein causes a genetic and metabolic reprogramming of the T cells, accelerating their exhaustion. "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."
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.