Cutting Edge: Induction of IFN-γ Production but Not Cytotoxicity by the Killer Cell Ig-Like Receptor KIR2DL4 (CD158d) in Resting NK Cells

Abstract Activated NK cells lyse tumor cells and virus-infected cells and produce IFN-γ upon contact with sensitive target cells. The regulation of these effector responses in resting NK cells is not well understood. We now describe a receptor, KIR2DL4, that has the unique property of inducing IFN-γ production, but not cytotoxicity, by resting NK cells in the absence of cytokines. In contrast, the NK cell-activation receptors CD16 and 2B4 induced cytotoxicity but not IFN-γ production. The induction by KIR2DL4 of IFN-γ production by resting NK cells was blocked by an inhibitor of the p38 mitogen-activated protein kinase signaling pathway, in contrast to the IL-2-induced IFN-γ secretion that was sensitive to inhibition of the extracellular signal-regulated kinase mitogen-activated protein kinase pathway. These results reveal a functional dichotomy (cytokine production vs cytotoxicity) in the response of resting NK cells, as dictated by the signals of individual receptors.