Moreover, we recently demonstrated that S. mansoni infection elicited the accumulation of unique CD4 + T cell populations exhibiting unconventional cytokine profiles in the liver, but not in the spleen, of mice infected during the transition phase, the period between early Th1- and late Th2-superior phases. These hepatic T cell populations produced the combinations of cytokines; IFN-c+IL-4 and IFN-c+IL-13. Furthermore, some of the unique populations simultaneously secreted IFN-c, IL4, and IL-13. We explored the previously unresolved molecular machineries underlying the accumulation of MCPHT cell populations in the liver during the transition phase of S. mansoni infection. The data presented here suggest that IL-18 induced during S. mansoni infection acts as a factor associated with the expansion of MCPHT cells. S. mansoni infection stimulated the elevation of IL18 levels not only in the sera but also in the liver during the transition phase, when the expansion of MCPHT cell populations and oviposition of the trematode begin. IL-18-deficient mice displayed severely impaired expansion of c4 and c13 cells in the liver during S. mansoni infection. Furthermore, expression of IL18R was observed in approximately half of both c4 and c13 cells. It is noteworthy that MCPHT cell populations were induced in IL-18KO mice at four weeks PI. The subsequent increase of these MCPHT cells was not induced in the IL-18KO mice, and this resulted in a considerable reduction in the proportions and the absolute numbers of c4 and c13 cells in IL-18KO mice compared to WT control mice at 6 weeks PI. This suggests that IL-18 is indispensable for the expansion, but not required for the generation, of c4 and c13 cells in the liver during S. mansoni infection. The determinant of the generation of MCPHT cells induced following S. mansoni infection are unknown. One possible candidate is an adolescent worm product. Indeed, soluble worm antigen preparation has been shown to endow conventional hepatic T cells with the capacity to produce large amounts of IL-4 and IL-13. SWAP consists of several components including not only T cell antigens but also factors that stimulate, or are targeted by innate immunity. It is probable that SWAP produced by immature and mature worms differs in its composition. Hence, the cytokine profiles of Th1 cells generated during the early phase of S. mansoni infection, when the antigens are presented by Kupffer cells affected by immature worm’s SWAP, may be converted into those of the MCPHT cells described here, induced during the transition phase, when the Kupffer cells influenced by mature worm’s SWAP present antigens. As the kinetics of the induction of MCPHT cells and fluke oviposition seem to be identical, the other possible candidate for the determinant of the generation MCPHT cells is soluble egg antigen, particularly omega-1, which is a glycosylated T2 RNase and most abundantly present in SEA.