HIF1 alpha is required for NK cell metabolic adaptation during virus infection

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 alpha (HIF1 alpha) is a feature of mouse NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF1 alpha-deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF1 alpha KO NK cells; however, their numbers were significantly reduced. Loss of HIF1 alpha did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found that HIF1 alpha-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 alpha-deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF1 alpha-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.