Activation of Vα14+ natural killer T cells by α-galactosylceramide results in development of Th1 response and local host resistance in mice infected with Cryptococcus neoformans

We examined the effect of alpha -galactosylceramide (alpha -GalCer) on the synthesis of gamma interferon (IFN-gamma) and local resistance in mice infected intravenously with Cryptococcus neoformans. The level of IFN-gamma in serum increased on day 3, reached a peak level on day 7, and decreased to the basal level on day 14 postinfection in mice treated with alpha -GalCer, while in vehicle-treated mice, no increase was detected at any time points except for a small increase on day 7. Such effects were not observed in NKT-KO mice. In CD4KO mice, minor synthesis of IFN-gamma was detected on day 3 in sera but was completely abolished by day 7. The alpha -GalCer-induced IFN-gamma production on day 3 was partially reduced in mice depleted of NK cells by treatment with anti-asialo-GM(1), antibody (Ab). Spleen cells obtained from infected and alpha -GalCer-treated mice on day 7 produced a large amount of IFN-gamma upon restimulation with live organisms, while only a marginal level of production was detected in splenocytes from infected and vehicle treated mice. Such effects were abolished in CD4KO and NKT-KO mice. Finally, the fungal loads in the lungs and spleen on days 7 and 14 were significantly reduced in alpha -GalCer-treated mice compared to those in control mice. In NKT-KO mice, local resistance elicited by alpha -GalCer was completely abolished, although no obvious exacerbation of infection was detected. Furthermore, treatment with anti-IFN-gamma monoclonal Ab mostly abrogated the protective effect of this agent. Thus, our results indicated that activation of V alpha 14(+) NKT cells resulted in an increased Th1 response and local resistance to C. neoformans through production of IFN-gamma.