Mitochondrial mass governs the extent of human T cell senescence.

Lauren A Callender,Arne N Akbar,Egle Solito,Elizabeth C Carroll,Emilia A Bober,Sian M Henson

doi:10.1111/acel.13067

Lauren A Callender, Arne N Akbar + Show 4 more

Open Access

https://doi.org/10.1111/acel.13067

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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.

Highlights

Using MitoTracker Green, a mitochondrial-specific dye that binds the mitochondrial membranes independently of mitochondrial membrane potential (MMP), we found the CD4+ EMRA subset isolated from middle-aged donors to have a significantly higher mitochondrial mass than CD8+ EMRAs, nearly double the amount of mitochondrial content (Figure 1b)
CD4+ EMRA T cells express higher levels of both the fatty acid translocase CD36 and the fatty acid transporters FATP2 and FATP3 (Figure 3d). These results suggest that the increased mitochondrial fitness of CD4+ EMRA T cells enables these cells to better utilize glucose and lipids, which may limit the impact of senescence
Senescent or EMRA T cells are a highly dynamic and heterogeneous subset of cells that accumulate with age (Callender et al, 2018) and are found in both the CD4+ and CD8+ T cell compartments

Summary

Introduction

(d) PGC1α expression in CD45RA/ CD27-defined EMRA T cell subsets from middle-aged donors. When we investigated the expression of PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), the key regulator of mitochondrial biogenesis, the CD4+ EMRA subset showed significantly higher ex vivo levels of this marker than the CD8+ EMRAs (Figure 1d). The increased ROS production seen in CD4+ EMRAs was neutralized owing to the higher mitochondrial mass, meaning that CD8+ EMRA T cells produced more ROS per mitochondria that can potentially enhance their senescent phenotype (Figure 2c).

Results

Conclusion