We have studied the relationship between B cell activation and the ability of IFN-gamma to inhibit B cell differentiation. The LPS activation of conventional and CD5+ B cells resulted in increased IFN-gamma R expression and increased the ability of IFN-gamma to inhibit LPS-induced B cell differentiation correlated with increased IFN-gamma R expression. We detected increased B cell IFN-gamma R expression 12 h after activation, and maximal IFN-gamma R expression was observed at 24 h. Activation of B cells by F(ab2)' anti-IgM induced a similar increase in IFN-gamma R expression. In autoimmune New Zealand Black mice, both conventional and CD5+ B cells showed a pattern of IFN-gamma R expression similar to that seen in DBA/2 mice, and both populations of B cells were sensitive to inhibition by IFN-gamma. To examine the role of IFN-gamma in the regulation of T cell-dependent B cell responses, we activated B cells with the CDC35 T cell line (which is specific for rabbit IgG). When rabbit anti-mouse Ig-treated B cells were activated by CDC35 T cells, we found that B cells exhibited increased IFN-gamma R expression by 48 h; we also found that IFN-gamma inhibited CDC35-mediated IgM secretion to a degree similar to IFN-gamma inhibition of T cell-independent B cell differentiation. Additionally, IFN-gamma inhibited CDC35-stimulated B cells even in the presence of exogenous IL-4 and IL-5. This study establishes the importance of IFN-gamma as a regulator of both T cell-independent and T cell-dependent B cell differentiation.