Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

The past five years has seen major progress in understanding the energy metabolic pathways used by different immune cell subpopulations. Cellular energy metabolism plays a fundamental role in dictating immune cell differentiation, homeostasis, and function. Natural killer (NK) cells are innate lymphocytes known for their ability to rapidly transition from resting to activated, then to exhausted states in response to external stimuli. These functional phases are accompanied by dynamic expression of immune effector molecules. In terms of energy metabolic pathways, effector T cells are highly glycolytic, while regulatory and memory T cells use fatty acid oxidation. NK cells undergo equivalent metabolic changes following cytokine activation. Similar to pro-inflammatory T-cell subsets, NK cells increase rates of glycolysis and OXPHOS and have substantially increased demand for glucose. While the role of metabolism has been extensively studied in the development and functional responses of T cells, similar studies in NK cells are lacking. We recently observed intracellular accumulation of lipids in NK cells in nutrient-deficient microenvironments. Importantly, this lipid-laden phenotype is associated with dysfunctional NK cell cytotoxicity. Based on these observations, we propose to study the fundamental metabolic programming of NK cells, including dynamic regulation of glycolysis, oxidative phosphorylation and fatty acid oxidation, in NK cell activation and differentiation. We hypothesize that this process is shaped by the availability of metabolic substrates in the microenvironment. We further hypothesize that this process depends upon the interplay between NK cell metabolic machinery and transcriptional pathways to determine immune cell signaling. To achieve this, our specific objectives are to characterize the metabolic profile of: 1) activated NK cells, 2) exhausted NK cells, 3) memory NK cells, and 4) to investigate the mechanism of metabolic regulation of NK cell function. Our studies will demonstrate that metabolic fuels used by NK cells are at the root of their function and address a critical gap in our knowledge of metabolic regulation of innate immunity.