Regulation of NK cell effector function by Acly

Natural Killer (NK) cells, crucial for viral immunity and tumor clearance, are influenced by metabolism. A prior study revealed that cytokine stimulation boosts the citrate-malate shuttle and cytosolic acetyl-CoA through ATP citrate lyase (ACLY) in NK cells. Acetyl-CoA is vital for fatty acid synthesis and protein acetylation, including histones. To explore the role of ACLY in NK cell function, we generated an inducible NK-specific Acly knockout mouse model. ACLY loss in NKp46+ NK cells did not alter maturation or IFN-γ production in naïve NK cells. However, ACLY-deficient NK cells exhibited notable proliferation defects in homeostatic and IL-15-stimulated conditions, associated with impaired glycolysis. The stimulation and priming of NK cells through IL-15 is an important mechanism for enhancing effector and anti-tumor functions. In addition to proliferation defect, IL-15-primed ACLY-deficient NK cells showed reduced IFN-γ responses to DAP12-associated activating receptors, specifically NKG2D, Ly49H, and Ly49D. RNA-seq revealed ACLY-deficient NK cells failed to upregulate DAP12 expression with IL-15 stimulation, confirmed at the protein level. These findings suggest the importance of ACLY in NK cell proliferation and potentially DAP12-driven effector functions. Ongoing experiments are focused on investigating how ACLY and cytosolic acetyl-CoA are linked to DAP12 expression, and the effects of this during in vivo effector functions.