Co-ligation of antigen receptor and complement receptor 2 (CD21) in the B cell membrane is important in the immune response to T-dependent antigens. Four CD21 ligands have so far been identified, but only the activated products of the third component of complement (C3) are known to augment the immune response to specific antigens. The most recently discovered ligand for CD21 is CD23. We have generated a CD32+ CD23+ fibroblast cell line which presents a surrogate antigen (anti-IgM) to human tonsil B cells in vitro. Incubation with these cells causes a 10- to 100-fold reduction in the threshold concentration of anti-IgM required for B cell proliferation. Anti-CD19 further enhances the response to antigen and induces proliferation in the absence of anti-IgM. Addition of soluble CD21 totally inhibits the effect of CD23, suggesting that CD21 mediates synergistic signaling by CD23.