Activation of Vα14+Natural Killer T Cells by α-Galactosylceramide Results in Development of Th1 Response and Local Host Resistance in Mice Infected withCryptococcus neoformans

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Abstract
We examined the effect of α-galactosylceramide (α-GalCer) on the synthesis of gamma interferon (IFN-γ) and local resistance in mice infected intravenously with Cryptococcus neoformans. The level of IFN-γ 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 α-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-γ was detected on day 3 in sera but was completely abolished by day 7. The α-GalCer-induced IFN-γ production on day 3 was partially reduced in mice depleted of NK cells by treatment with anti-asialo-GM1 antibody (Ab). Spleen cells obtained from infected and α-GalCer-treated mice on day 7 produced a large amount of IFN-γ 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 α-GalCer-treated mice compared to those in control mice. In NKT-KO mice, local resistance elicited by α-GalCer was completely abolished, although no obvious exacerbation of infection was detected. Furthermore, treatment with anti-IFN-γ monoclonal Ab mostly abrogated the protective effect of this agent. Thus, our results indicated that activation of Vα14+ NKT cells resulted in an increased Th1 response and local resistance to C. neoformans through production of IFN-γ.