Hypoxia inducible factor-1a drives metabolic adaptation of natural killer cells during pathogen infection

Abstract Natural killer (NK) cells provide an early response to pathogen infection, limiting host morbidity and lethality. This response requires NK cells to adapt due to the energy demands of activation and biosynthesis. We found that NK cells upregulate the metabolic adaptor hypoxia inducible factor-1a (HIF-1a) during murine cytomegalovirus (MCMV) infection in vivo. Specific deletion of HIF-1a in NK cells impaired their ability to reduce viral load and protect against morbidity. While HIF-1a-deficient NK cells had no defects in effector functions, their numbers were significantly reduced during early responses and there was blunted expansion of Ly49H+ NK cells. However, NK cell proliferation per se was not impaired during in vivo infection and in vitro cytokine stimulation. Instead, we found that the absence of HIF-1a impaired glucose metabolism and up-regulated the pro-apoptotic protein Bim during cytokine stimulation in vitro. Furthermore, during MCMV infection in vivo HIF1a-deficient NK cells upregulated Bim and had increased caspase activity. Thus, HIF-1a normally drives glucose metabolism and represses Bim expression during pathogen infection to sustain NK cell numbers for an optimal response.