Metabolic Regulation of Natural Killer Cell IFN-γ Production

Metabolism is critical for a host of cellular functions and provides a source of intracellular energy. It has been recognized recently that metabolism also regulates differentiation and effector functions of immune cells. Although initial work in this field has focused largely on T lymphocytes, recent studies have demonstrated metabolic control of innate immune cells, including natural killer (NK) cells. Here, we review what is known regarding the metabolic requirements for NK cell activation, focusing on NK cell production of interferon-gamma (IFN-γ). NK cells are innate immune lymphocytes that are poised for rapid activation during the early immune response. Although their basal metabolic rates do not change with short-term activation, they exhibit specific metabolic requirements for activation depending upon the stimulus received. These metabolic requirements for NK cell activation are altered by culturing NK cells with interleukin-15, which increases NK cell metabolic rates at baseline and shifts them toward aerobic glycolysis. We discuss the metabolic pathways important for NK cell production of IFN-γ protein and potential mechanisms whereby metabolism regulates NK cell function.