The antioxidant glutathione as a regulator of natural killer cell immunity

Natural killer (NK) cells are cytotoxic lymphocytes that belong to the innate branch of the immune system. Regulation of NK cell activity relies on the expression and engagement of a wide range of inhibitory and activating receptors that detect signals arising from cells in distress. Besides their cytotoxic function, NK cells are effective producers of cytokines that participate in the regulation of other immune cells, such as dendritic cells and T cells. These innate lymphocytes control microbial infections and malignant cell growth, which are pathological conditions where reactive oxygen species (ROS) play a crucial role. ROS participate in cell signaling events and constitute important secondary messengers for immune cell proliferation and growth. However, when accumulated, their presence leads to oxidative stress due to their high reactivity against biomolecules. In order to ensure coordinated levels of ROS, cells are endowed of antioxidant systems that allow for ROS detoxification. One of the most important intracellular antioxidants is glutathione (GSH). Given the subset specificity of GSH regulation in immunity, we aimed to investigate the role of this antioxidant in NK cells. Using a genetic-based approach, through a flox-Cre system, we specifically abrogated GSH production in NK cells. Mutant mice had a reduced abundance of NK cells, when compared to controls. Furthermore, in vitro stimulation of NK cells with IL-15, showed that ablation of GSH production renders NK cells unable to proliferate and these cells were less cytotoxic. NK cells lacking GSH accumulated mitochondrial ROS, resulting in reduced mitochondrial fitness. This was paralleled by a general metabolic shutdown, and reduced mTOR and STAT5 signaling. In vivo, GSH and redox regulation were demonstrated to be key for NK cell-mediated regulation of T cells, in a viral model of lymphocytic choriomeningitis virus (LCMV). Moreover, in an experimental tumor model, deletion of GSH resulted in an NK cell intrinsic impairment of tumor dissemination and increased exhaustion. Taken together, our results indicate GSH as a key checkpoint for NK cell homeostasis and function.