Cox10-deficient NK cells have increased apoptosis during MCMV infection, leading to susceptibility

Abstract

Abstract Studies in diverse cell types have rediscovered the importance of basic cellular metabolism in regulating immune responses. For example, glycolytic and oxidative metabolism are counter-regulated in T cells to develop inflammatory effectors vs. memory and regulatory cells, respectively. NK cells, which are first responders to viral infection and malignant transformation, may be similarly regulated. We recently showed that NK cell cytotoxic activity during infection with murine cytomegalovirus (MCMV) required glucose metabolism, whereas other NK cell responses such as cytokine production did not. We hypothesized that oxidative metabolism would be required for some of these glycolysis-independent responses. To test this, we examined responses to MCMV in mice with an NK-specific deletion of Cox10, which is required for assembly of electron transport chain complex IV. These “Ncr1-Cox10” mice had normal NK cell development and numbers, and stimulated Cox10-deficient NK cells survived and proliferated normally in vitro. However, Ncr1-Cox10 mice were more susceptible to MCMV infection, with impaired expansion of MCMV-specific Ly49H+ NK cells and increased apoptosis of splenic NK cells. Thus, we find that Cox10 is required by NK cells to expand and survive in response to MCMV infection. These deficiencies were not found in vitro, emphasizing the importance of using NK-specific genetic models to investigate metabolism in physiological contexts.