NK cells eliminate Cryptococcus neoformans by potentiating the fungicidal activity of macrophages rather than by directly killing them upon stimulation with IL-12 and IL-18

In the present study, we examined whether natural killer (NK) cells have di rect fungicidal activity against Cryptococcus neoformans. Splenic NK cells were obtained from SCID mice and stimulated with a combination of interleuk in (IL)-12 and IL-18 in hat culture plates or round tubes. They were then o r at the same time cultured with the yeast cells and the number of viable y east cells was examined. We could not detect direct fungicidal activity by NK cells under any culture condition, although they produced a large amount of IFN-gamma and exerted marked cytotoxic activity against YAC-1 cells. On the other hand, NK cells significantly potentiated the nitric oxide-mediat ed cryptococcocidal activity of thioglycolate-elicited peritoneal macrophag es obtained from SCID mice upon stimulation with IL-12 and IL-18, The cultu re supernatants of NK cells stimulated with IL-12 and IL-18 provided simila r results when used in place of NK cells. The induction of macrophage antic ryptococcal activity by NK cells and NK cell culture supernatants were both mediated by IFN-gamma because the specific mAb almost completely abrogated such effect. Considered collectively, our results suggested that NK cells may play a regulatory role in potentiating macrophage-mediated fungicidal m echanisms in host resistance to infection with C, neoformans rather than ex erting a direct killing activity against the fungal pathogen.