Mitochondrial mass governs the extent of T cell senescence

Abstract

The susceptibility of human CD4+ and CD8+ T cells to senesce differs, with CD8+ T cells acquiring an immunosenescent phenotype faster than the CD4+ T cell compartment. We show here that it is the inherent difference in mitochondrial content that drives this phenotype, with senescent human CD4+ T cells displaying a higher mitochondrial mass. The loss of mitochondria in the senescent human CD8+ T cells has knock‐on consequences for nutrient usage, metabolism and function. Senescent CD4+ T cells uptake more lipid and glucose than their CD8+ counterparts, leading to a greater metabolic versatility engaging either an oxidative or a glycolytic metabolism. The enhanced metabolic advantage of senescent CD4+ T cells allows for more proliferation and migration than observed in the senescent CD8+ subset. Mitochondrial dysfunction has been linked to both cellular senescence and aging; however, it is still unclear whether mitochondria play a causal role in senescence. Our data show that reducing mitochondrial function in human CD4+ T cells, through the addition of low‐dose rotenone, causes the generation of a CD4+ T cell with a CD8+‐like phenotype. Therefore, we wish to propose that it is the inherent metabolic stability that governs the susceptibility to an immunosenescent phenotype.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease

“…This phenotype may be indicative of T cell exhaustion and is typically observed in chronic viral infection (463). Increased mitochondrial mass: Suggests impaired mitochondrial and glycolytic metabolism in ME/CFS T cell subsets (464).…”

Mitochondrial Dysfunction Accelerates Ageing

“…Indeed, we have shown that human CD8 + T cells were more susceptible to senescence compared to their CD4 + counterparts as they displayed a lower mitochondrial content and postulated loss of mitochondrial function controls the senescence phenotype in T cells [4] as well as other cell types [5,6]. However the mechanism remained elusive, that is until the recent paper by Desdin-Mico et al published in Science demonstrated that mitochondrial dysfunction was controlled by mitochondrial transcription factor A (TFAM) [7].…”