Mitochondrial mass governs the extent of human T cell senescence

Abstract

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.