Caught in the cROSsfire: GSH Controls T Cell Metabolic Reprogramming

Abstract

T cell activation and proliferation critical for protective immunity depend on appropriate rewiring of cellular metabolism. In this issue of Immunity, Mak et al. (2017) show that the antioxidant gluthathione (GSH) controls reactive oxygen species (ROS)-dependent engagement of metabolic signaling pathways that lead to protective T cell responses.

Figure 1. TCR Activation in WT Cells Leads to an Increase in Cellular ROS Concentrations that Can Be Buffered by the Antioxidant GSH

GSH synthesis increases after TCR activation through transcriptional induction of the glutamate cysteine ligase catalytic subunit (GCLC). GSH limits ROS activity to allow ROS-dependent activation of NFAT, but also prevents excessive ROS accumulation that can have damaging side effects. GSH-mediated buffering allows for activation of the critical metabolic mediators calcium-dependent calcineurin, NFAT, Myc, and mTOR. This in turn rewires metabolism and increases aerobic glycolysis and glutamine import, to support biomass generation for cell growth and proliferation. TCR activation in Gclc^−/− T cells leads to an increase in cellular concentrations of ROS, which can no longer be adequately buffered. Increased ROS concentrations interferes with activation of NFAT, Myc, and mTOR. Failure to induce enhanced glycolysis and glutamine import in Gclc^−/− T cells leads to reduced cell growth and proliferation. Proper metabolic remodeling is essential for the formation of protective immune responses in vivo.