Mice infected with Schistosoma mansoni develop polarized Th2 responses in which Th1 responses are prevented by IL-10-mediated suppression of IL-12 production. We show that dendritic cells from infected mice are primed to make IL-12 in response to CD40 ligation, and that IL-10 acts by inhibiting this process. In infected mice, two subpopulations of CD4+ cells, separable by their expression of CD25, make IL-10. CD25+ CD4+ cells expressed forkhead box P3, inhibited proliferation of CD4+ T cells, and made IL-10, but little IL-5. In contrast, CD25− CD4+ cells failed to express forkhead box P3 or to inhibit proliferation and accounted for all the IL-5, IL-6, and IL-13 produced by unseparated splenic populations. Thus, CD25+ and CD25− subpopulations could be characterized as regulatory T cells (Treg cells) and Th2 cells, respectively. Consistent with their ability to make IL-10, both CD25+ and CD25− CD4+ T cells from infected mice were able, when stimulated with egg Ag, to suppress IL-12 production by CD40 agonist-stimulated dendritic cells. Additionally, in adoptive transfer experiments, both CD4+ subpopulations of cells were able to partially inhibit the development of Th1 responses in egg-immunized IL-10−/− mice. The relationship of Treg cells in infected mice to natural Treg cells was strongly suggested by the ability of CD25+ CD4+ cells from naive mice to inhibit Th1 response development when transferred into egg-immunized or infected IL-10−/− mice. The data suggest that natural Treg cells and, to a lesser extent, Th2 cells play roles in suppressing Th1 responses and ensuring Th2 polarization during schistosomiasis.