Metabolic Regulation of Natural Killer Cell Activation

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Project Summary The long-term goal of this project is to determine the metabolic regulation of NK cell effector functions to improve our understanding of basic mechanisms of NK cell activation in health and disease. Natural killer (NK) cells are innate immune lymphocytes that serve as a critical first line defense against infection, particularly viruses, and are important for tumor immunosurveillance. NK cells mediate their effects via two mechanisms: production of cytokines (especially IFN-gamma) and target cell killing. NK cell effector functions can be triggered by inflammatory cytokines or engagement of germline-encoded activating receptors whose ligands are displayed by infected and/or tumor cells. Metabolic regulation plays a key role in many aspects of immunity, including in NK cell response to viral infection. We previously demonstrated that stimulation of naïve, fresh NK cells through cytokines versus activating receptors has differential metabolic requirements, with activating receptor stimulation exquisitely sensitive to inhibition of glucose-driven oxidative phosphorylation (OXPHOS). IL-15 priming of NK cells can overcome metabolic requirements for NK cell effector functions in vitro and in vivo, leading to metabolic flexibility evident as the ability to efficiently function in the face of inhibition of key metabolic pathways. Our preliminary studies demonstrate activation-dependent differences in the metabolic fuels and pathways required for NK cell effector functions in vitro and in vivo that change with cytokine priming. We are interested in how cytokine priming leads to this metabolic `flexibility', with a long-term goal of applying this knowledge to strategies for NK cell therapies. This proposal presents a 5 year plan to investigate the metabolic regulation of NK cell activation. The specific aims of this proposal are to investigate: 1) metabolic pathways upregulated during cytokine priming and the effects of glucose metabolism, 2) transcription factors regulating production of cytokine transcript in primed NK cells, and 3) metabolic flexibility dependent on mTOR. We will use new inducible models with NK-specific deletion of key regulators of metabolic pathways to rigorously test our hypotheses. The studies proposed here will advance our understanding of how NK cells can be primed for metabolic flexibility and metabolic mechanisms important for NK cell effector function, with a long-term goal of optimizing strategies to target NK cells for therapy of human disease.