Interleukin-10 (IL-10) and transforming growth factor- (TGF-) regulate CD4⁺ T cell interferon- (IFN-) secretion in schistosome granulomas. The role of IL-12 was determined using C57BL/6 and CBA mice. C57BL/6 IL-4 / granuloma cells were stimulated to produce IFN- when cultured with IL-10 or TGF- neutralizing monoclonal antibody. In comparison, C57BL/6 wild-type (WT) control granuloma cells produced less IFN-. IL-12, IL-18, and soluble egg antigen stimulated IFN- release from C57BL/6 IL-4 / and WT mice. IFN- production in C57 IL-4 / and WT granulomas was IL-12 dependent, because IL-12 blockade partly abrogated IFN- secretion after stimulation. All granuloma cells released IL-12 (p70 and p40), and IL-12 production remained constant after anti-TGF-, anti-IL-10, recombinant IL-18, or antigen stimulation. C57 WT and IL-4 / mouse granuloma cells expressed IL-12 receptor (IL-12R) 1-subunit mRNA but little 2 mRNA. TGF- or IL-10 blockade did not influence 1 or 2 mRNA expression. CBA mouse dispersed granuloma cells released no measurable IFN-, produced IL-12 p70 and little p40, and expressed IL-12R 2 and little 1 mRNA. In T helper 2 (Th2) granulomas of C57BL/6 WT and IL-4 / mice, cells produce IL-12 (for IFN- production) and IL-10 and TGF- modulate IFN- secretion via mechanisms independent of IL-12 and IL-12R mRNA regulation. We found substantial differences in control of granuloma IFN- production and IL-12 circuitry in C57BL/6 and CBA mice.