The polyclonal B cell activation is the earliest and most common immunologic abnormality in lupus-prone mice. However, its cellular mechanism(s) has not been well defined. To determine the contribution of CD4+ T cells in this immunologic abnormality, we have depleted CD4+ T cells in lupus-prone (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice by treating them with anti-CD4 mAb from birth and determined the development of IgM and IgG polyclonal antibody formation. Our results indicate that first, different mechanisms control the development of IgM polyclonal B cell activation in these two autoimmune mice; in (NZB x NZW)F1 mice, IgM polyclonal B cell activation is likely to be a result of an intrinsic B cell defect, whereas CD4+ T cells seem to be responsible for this immunologic abnormality in MRL/MpJ-lpr/lpr mice. Second, the increased production of IgG antibodies, including the IgG3 subclass, was totally regulated by CD4+ T cells in both autoimmune mice. Because IgG3 antibodies can be highly nephritogenic, independent of their immunologic specificities, which is the result of the antibodies' cryoglobulin activity, the active role of CD4+ T cells in the production of IgG3 antibodies in lupus-prone autoimmune mice further strengthens the implication of CD4+ T cells in murine systemic lupus erythematosus.