IL-18 with IL-2 protects against Strongyloides venezuelensis infection by activating mucosal mast cell–dependent type 2 innate immunity

C57BL/6 (B6) and B6 background STAT6(−/−) mice pretreated with IL-18 plus IL-2 showed prominent intestinal mastocytosis and rapidly expelled implanted adult worms of the gastrointestinal nematode Strongyloides venezuelensis. In contrast, identically pretreated mast cell–deficient W/W(v) mice failed to do so. Thus, activated mucosal mast cells (MMC) are crucial for parasite expulsion. B6 mice infected with S. venezuelensis third-stage larvae (L3) completed parasite expulsion by day 12 after infection, whereas IL-18(−/−) or IL-18Rα (−/−) B6 mice exhibited marked impairment in parasite expulsion, suggesting a substantial contribution of IL-18–dependent MMC activation to parasite expulsion. Compared with IL-18(−/−) or IL-18Rα (−/−) mice, S. venezuelensis L3–infected STAT6(−/−) mice have poorly activated MMC and sustained infection; although their IL-18 production is normal. Neutralization of IL-18 and IL-2 further reduces expulsion in infected STAT6(−/−) mice. These results suggest that collaboration between IL-18–dependent and Th2 cell–dependent mastocytosis is important for prompt parasite expulsion.