Immunization with human collagen IV has been shown to lead to the selective activation of Th-1 and Th-2-like cells in vivo depending on the I-A genotype of the mice. Mice expressing I-As generate Th-1 cells, and mice expressing I-Ab generate Th-2 cells after immunization. We examined the response of (bxs)F1 hybrid mice to determine the types of CD4 T cell activated. We found that Th-1-like responses dominated, in that CD4 T cells from human collagen IV-primed mice displayed good proliferative responses and little ability to induce antibody formation, and secreted IFN-gamma and not IL-5. Most of the Th-1-like activity of F1 hybrid T cells was I-As restricted. Inhibition of Th-1 cell priming using anti-I-As antibody administered with the priming Ag in vivo revealed Th-2-like activity, in that the CD4 T cells now secreted IL-5 and not IFN-gamma and induced antibody formation. Additional studies indicated that anti-IFN-gamma treatment in vivo also revealed Th-2 cells, suggesting that I-As-restricted CD4 T cells producing or controlling the production of IFN-gamma suppress Th-2 priming.