NK cell metabolic adaptation to infection promotes survival and viral clearance

Natural killer (NK) cells are essential for early protection against virus infection, and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia inducible factor-1 (HIF-1) is a feature of NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF-1-deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF-1 KO NK cells however, their numbers were significantly reduced. Loss of HIF-1 did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found HIF1-deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF1-deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF-1-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.