Essential role of IL-12 signaling for NK cell expansion and memory formation during viral infection (160.15)

Abstract

Abstract Although natural killer (NK) cells are generally classified as innate immune cells, several recent studies demonstrated that NK cells become long-lived memory cells and contribute to secondary immune responses like T and B cells. However, the precise signals that promote generation of long-lived NK cells are unknown. Using cytokine receptor deficient mice, we show that the pro-inflammatory cytokine IL-12 is indispensible for virus-specific NK cell expansion and generation of memory cells during MCMV infection. In contrast to wildtype NK cells which proliferated robustly and resided in lymphoid and non-lymphoid tissues for months following MCMV infection, IL-12 receptor-deficient NK cells failed to expand and were difficult to detect soon after infection. In the absence of IL-12 signaling, NK cells were also unable to mediate protection following MCMV challenge. We have evidence that a STAT4-dependent, IFN-gamma-independent mechanism contributes toward the generation of memory NK cells during viral infection. Understanding the full contribution of inflammatory cytokine signaling in the NK cell response to viral infection will be of interest for development of vaccines and therapeutics.