Glutathione is critical for NK cell-mediated immunity.

Natural killer (NK) cells are essential for immune protection against tumors and viruses. Disease environments impose oxidative stress and impair immune cell functions. Glutathione (GSH) is a major cellular antioxidant and is critical for the immune response, but how it modulates NK cell function remains largely unknown. Using a mouse model with a specific deletion of the catalytic subunit of glutamate-cysteine ligase (Gclc) in NK cells, we demonstrate that GSH supports interleukin-15 (IL-15)-driven activation of NK cells. Gclc deficiency causes an intracellular accumulation of reactive oxygen species (ROS), which impairs the metabolism of NK cells. This is accompanied by defective proliferation and cytokine production concurrent with subverted mTOR and STAT5 activation. During acute lymphocytic choriomeningitis virus (LCMV) infection, Gclc-deficient NK cells are unable to suppress the antiviral T cell response. Remarkably, Gclc deficiency impairs NK cell-mediated protection against tumor lung metastases. Our findings highlight an essential role of GSH in maintaining NK cell functionality.