A Critical Role for IL-18 in the Proliferation and Activation of NK1.1+CD3− Cells

Like IL-12, IFN-γ-inducing factor/IL-18 has been shown to stimulate T cells for IFN-γ production and growth promotion. Considering the NK-stimulatory capacity of IL-12, we investigated the effect of IL-18 on NK lineage cells. A CD4 − CD8 − surface Ig − Ia − fraction of freshly prepared C57BL/6 spleen cells proliferated strikingly in response to combinations of IL-12 + IL-18 or IL-2 + IL-18, but not to the individual cytokines or IL-2 + IL-12. Cells proliferating in response to IL-2 + IL-18 were NK1.1 + CD3 − , whereas IL-12 + IL-18-responsive cells were NK1.1 − CD3 − . Restimulation of the former cells with IL-12 + IL-18 or the latter cells with IL-2 + IL-18 resulted in the generation of NK1.1 − CD3 − or NK1.1 + CD3 − cells, respectively. Moreover, a NK1.1 + CD3 − CD4 − CD8 − surface Ig − Ia − population isolated from spleen cells was found to form NK1.1 + CD3 − or NK1.1 − CD3 − blasts by stimulation with IL-2 + IL-18 or IL-12 + IL-18, respectively, and the NK1.1 positivity on these blasts was again reversed after restimulation with an alternative combined stimulus. Both types of blasts produced enormously large amounts of IFN-γ in response to IL-12 + IL-18 and exhibited strikingly high levels of NK activity. These results indicate that IL-18 plays an obligatory role in inducing proliferation and activation of NK1.1 + CD3 − CD4 − CD8 − cells and that the expression of the NK1.1 marker is reversible, depending on the cytokine used for stimulation in combination with IL-18.