Sensitivity to restimulation-induced cell death is linked to glycolytic metabolism in human T cells

Abstract

Abstract Restimulation-induced cell death (RICD) helps to regulate immune responses by setting an upper threshold for effector T cell expansion and limiting nonspecific damage to the host. RICD is triggered by re-engagement of the T cell receptor (TCR) on a cycling, activated T cell, resulting in apoptosis. However, it remains unclear how RICD sensitivity is calibrated in T cells derived from different individuals and subsets. As effector T cells expand and become responsive to RICD, they have also switched from a quiescent metabolic state into active aerobic glycolysis (Warburg effect). We hypothesized that in addition to facilitating proliferation and effector function, metabolic programming directly influences RICD sensitivity. We found that secretion of L-lactate, the end product of glycolysis, positively correlated with greater RICD sensitivity in CD8+ effector T cells from different human donors. Strikingly, replacing glucose in culture media for galactose, which results in almost exclusive use of oxidative phosphorylation (OXPHOS), rendered T cells significantly less sensitive to RICD. Consistent with this, blocking glycolysis with 2-deoxy-glucose (2-DG) significantly reduced RICD sensitivity, while inhibiting OXPHOS increased RICD sensitivity. Glycolysis promoted RICD sensitivity in part through mTOR signaling. Moreover, we found that active glycolysis facilitated induction of pro-apoptotic effector molecules like Fas ligand upon TCR restimulation, which was blocked with 2-DG treatment. Collectively, these data suggest that RICD susceptibility is dependent on glycolytic metabolism in effector T cells, and that switching back to OXPHOS may help shield cells transitioning into the memory pool from RICD.