Dominant type-1 cytokine production is induced in a murine model of systemic histoplasmosis. We used this model to investigate whether the presence of antagonistic cytokines during T cell priming changes the polarity of T cells in response to Histoplasma infection. Before infection with Histoplasma capsulatum, mice were injected twice with goat anti-mouse IgD antiserum (GalphaMdelta), which induced expression of dominant type-2 cytokines. At days 7 and 14 after infection, the GalphaMdelta-treated mice had suppressed IFN-gamma response and a significantly greater fungal burden in their spleens and lungs. The number of IFN-gamma-producing cells as well as the level of IFN-gamma produced per cell was greatly reduced. Not only CD4+ T cells but also CD8+ T cells were affected. The number of Histoplasma-induced IFN-gamma-producing cells was partially restored in GalphaMdelta-treated IL-4-/- and IL-10-/- mice and completely restored in IL-4-/- IL-10-/- mice. Thus, the combined effect of IL-4 and IL-10 suppressed the generation of IFN-gamma-producing cells. A longitudinal study demonstrated that as IL-4 and IL-10 decreased, the number of Histoplasma-induced IFN-gamma-producing cells rapidly increased, and fungal clearance improved, demonstrating that the presence of IL-4 and IL-10 did not permanently change the polarity of T cells.