Generation of NK cell memory requires IL-12 and STAT4 signaling (45.3)

Abstract

Abstract Recent studies have demonstrated that natural killer (NK) cells can become long-lived and can contribute to secondary immune responses like T and B cells; however, the precise signals that promote the generation of these long-lived memory NK cells remain unknown. Using cytokine receptor deficient mice we investigated the role of cytokine IL-12 in the activation, expansion, and generation of the virus-specific NK cell response to mouse cytomegalovirus (MCMV) infection. We demonstrate that IL-12 receptor-deficient NK cells exhibit a profound expansion defect following MCMV infection. This defect extended to the formation of long-lived memory cells, as IL-12 receptor-deficient NK cells were undetectable 2 weeks after infection whereas wildtype NK cells proliferated robustly and generated long-lived cells detectable months after MCMV infection. These findings were corroborated through the use of mice deficient in STAT4, which exhibited a defect in the expansion and formation of long-lived memory cells compared to wildtype NK cells in a competitive setting. This work demonstrates a key role for IL-12 and STAT4 during NK cell priming, and describes the requirements for generating robust virus-specific NK cell memory. Understanding the full contribution of inflammatory cytokines and the signals necessary for a long-lived NK cell response against viral infection will be of interest in the development of vaccines and therapeutics.