Activation-specific metabolic regulation of NK cell IFN-gamma production (INC6P.334)

Abstract

Abstract Many factors that stimulate NK cell functional responses have been described; however metabolic fuels that drive NK cell function are unknown. Metabolism is significantly altered in disease states and metabolic regulation of T cell function is well-described. We hypothesize that NK cells require distinct metabolic fuels for survival, proliferation, and functional responses. NK cell metabolic phenotype was determined with an extracellular flux analyzer to determine basal oxidative phosphorylation (oxphos) and glycolysis of resting and activated NK cells. NK cells were then cultured under a variety of conditions using inhibitors and nutrient deprivation to determine cellular requirements for glucose, fatty acids, and oxphos for NK cell survival, proliferation, and function. NK cells primarily utilize oxphos at baseline and, in contrast to T cells, upon proliferation. However, there is significant plasticity in the metabolic requirements for NK cell IFN-gamma production. NK cell IFN-gamma production in response to cytokine stimulation is not dependent on either glycolysis or oxphos. By contrast, NK cell IFN-gamma production in response to receptor stimulation requires oxphos and is partially dependent on glycolysis. The metabolic requirements for NK cell IFN-gamma production are not altered by priming in vitro or in vivo, but do change with proliferation. These findings suggest that the metabolic microenvironment in vivo may significantly alter NK cell function.