Amino acid-dependant mTORC1 and cMyc signaling is essential for Natural Killer cell metabolic and functional responses

Abstract

Natural killer [NK) cells are innate cytotoxic lymphocytes that are essential to the immune response against virally infected and transformed cells. NK cells directly kill target cells through the release cytotoxic granules. In addition, they can orchestrate an adaptive immune response through the release of proinflammatory cytokines. While the concept of immunometabolism has been recognized as critical in dictating the response of several immune cell subsets, nothing is currently known regarding the regulation of NK cell metabolism. In this study, we examined the changes that occur in NK cell metabolism following activation and determined the importance of cellular metabolism in controlling NK cell effector functions. Our findings reveal the dramatic metabolic changes that occur following NK cell activation; cytokine-activated NK cells significantly increase their rates of glycolysis and OxPhos. This increase in metabolism corresponds with complete metabolic reprogramming, where the mRNA expression of key glycolytic genes was significantly increased in NK cells following cytokine stimulation. Furthermore, this metabolic response was shown to be important in controlling the acquisition of NK cell effector functions; direct perturbations to the rate of glycolysis decreased NK cell effector molecule production.