NK Cell–Like Behavior of Vα14i NK T Cells during MCMV Infection

Abstract

Immunity to the murine cytomegalovirus (MCMV) is critically dependent on the innate response for initial containment of viral replication, resolution of active infection, and proper induction of the adaptive phase of the anti-viral response. In contrast to NK cells, the Vα14 invariant natural killer T cell response to MCMV has not been examined. We found that Vα14i NK T cells become activated and produce significant levels of IFN-γ, but do not proliferate or produce IL-4 following MCMV infection. In vivo treatment with an anti-CD1d mAb and adoptive transfer of Vα14i NK T cells into MCMV-infected CD1d^−/− mice demonstrate that CD1d is dispensable for Vα14i NK T cell activation. In contrast, both IFN-α/β and IL-12 are required for optimal activation. Vα14i NK T cell–derived IFN-γ is partially dependent on IFN-α/β but highly dependent on IL-12. Vα14i NK T cells contribute to the immune response to MCMV and amplify NK cell–derived IFN-γ. Importantly, mortality is increased in CD1d^−/− mice in response to high dose MCMV infection when compared to heterozygote littermate controls. Collectively, these findings illustrate the plasticity of Vα14i NK T cells that act as effector T cells during bacterial infection, but have NK cell–like behavior during the innate immune response to MCMV infection. An efficient immune response to viral infection requires both innate and adaptive immune cells. Natural killer (NK) cells are a critical innate cellular component of the immune response to murine cytomegalovirus (MCMV). Natural killer T (NK T) cells are non-classical T cells that have the potential to bridge the two arms of the immune system. However, the contribution of NK T cells to the anti-viral immune response has not been extensively studied. In the absence of additional stimuli, NK T cells actively participate in the immune response to MCMV infection. Interestingly, in contrast to their response to bacteria, we demonstrate that only the innate NK T cell arm is activated during viral infection while the adaptive branch, TCR engagement by CD1d, is dispensable. NK T cells display signs of activation in response to viral infection, increased expression of CD25, a rapid decrease in cell number, and production of the anti-viral cytokine IFN-γ. The NK T cell response to MCMV also influences the NK cell activity and the inflammatory cytokine profiles. Understanding the physiological function of these unique T cells in the context of infection will aid in the development of novel therapeutic and preventive treatments for viral infections.