A CRITICAL ROLE FOR IL-18 IN THE PROLIFERATION AND ACTIVATION OF NK1.1(-) CELLS()CD3()

Like IL-12, IFN-gamma-inducing factor/IL-18 has been shown to stimulat e T cells for IFN-gamma production and growth promotion. Considering t he 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 respo nse to combinations of IL-12 + IL-18 or IL-2 + IL-18, but not to the i ndividual cytokines or IL-2 + IL-12, Cells proliferating in response t o IL-2 + IL-18 were NK1.1(+)CD3(-), whereas IL-12 + IL-18-responsive c ells 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 generat ion of NK1.1(-)CD3(-) or NK1.1(+)CD3(-) cells, respectively. Moreover, a NK1.1(-)CD3(-)CD4(-)CD8(-) surface Ig(-)Ia(-) population isolated f rom spleen cells was found to form NK1.1(+)CD3(-) or NK1.1(-)CD3(-) bl asts 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 rest imulation with an alternative combined stimulus. Both types of blasts produced enormously large amounts of IFN-gamma in response to IL-12 IL-18 and exhibited strikingly high levels of NK activity. These resul ts indicate that IL-18 plays an obligatory role in inducing proliferat ion and activation of NK1.1(+)CD3(-)CD4(-)CD8(-) cells and that the ex pression of the NK1.1 marker is reversible, depending on the cytokine used for stimulation in combination with IL-18.