Enhanced gamma interferon production through activation of V alpha 14(+) natural killer T cells by alpha-galactosylceramide in interleukin-18-deficient mice with systemic cryptococcosis

We showed recently that activation of Va14(+) natural killer T cells (NKT c ells) by alpha -galactosylceramide (alpha -GalCer) resulted in increased ga mma interferon (IFN-gamma) production and host resistance to intravenous in fection with Cryptococcus neoformans. In other studies, interleukin-18 (IL- 18) activated NKT cells in collaboration with IL-12, suggesting the possibl e contribution of this cytokine to alpha -GalCer-induced IFN-gamma synthesi s. Here we examined the role of IL-18 in alpha -GalCer-induced Th1 response by using IL-18KO mice with this infection. In these mice, levels of IFN-ga mma in serum and its synthesis in vitro by spleen cells stimulated with liv e organisms were not reduced, but rather enhanced, compared to those in wil d-type (WT) mice, while such production was completely absent in IL-12KO mi ce. The enhanced production of IFN-T correlated with increased IL-12 synthe sis but not with reduced production of IL-4, which was rather increased. IF N-gamma synthesis in IL-18KO mice was abolished by neutralizing anti-IL-12 antibody and significantly inhibited by neutralization of endogenous IL-4 w ith a specific monoclonal antibody. In addition, administration of recombin ant IL-4 significantly enhanced the production of IFN-gamma in WT mice. Fin ally, the enhanced production of IFN-gamma in IL-18KO mice correlated with increased host defense against cryptococcal infection, as indicated by enha ncement in alpha -GalCer-related clearance of microorganisms. Our results i ndicated that in IL-18KO mice, IFN-gamma synthesis was enhanced through ove rproduction of IL-12 and IL-4 after intravenous infection with C. neoforman s and a ligand-specific activation of V alpha 14(+) NKT cells.