Activation of B cells by anti-CD40 provides an excellent model to investigate the direct effect of various cytokines on Ig production. Using this culture system, we examined the effect of IL-2 alone or in combination with other cytokines. IL-2 alone had only a moderate effect on Ig production by anti-CD40-activated B cells if compared with the effect of IL-10. However, IL-2 significantly augmented the synthesis of IgM, IgA, and IgG, including all IgG subclasses by anti-CD40-activated B cells cultured in the presence of IL-10. Both IgD- and IgD+ B cells showed an increase of IL-10-induced Ig production if IL-2 was added to the culture. The addition of IL-2 also increased immunoglobulin synthesis by anti-CD40/IL-10-activated B cells from patients with common variable immunodeficiency (CVI) and defective IL-2 production, suggesting that in a subgroup of CVI patients the IL-2 deficiency may contribute to the observed hypogammaglobulinemia. In contrast, the addition of IL-2 had a suppressive effect on IgE and IgG4 production by B cells cultured in the presence of anti-CD40 and IL-4. These data demonstrate that IL-2 plays an active role in the regulation of Ig production via CD40 by anti-CD40-activated B cells.