We investigated the role of gp39-CD40 interaction in the development of glomerulonephritis in lupus mice. In contrast to normal mice, lupus mice had much higher percentages of intensely gp39+ T cells in their spleens even at the preautoimmune age of 1 mo, and the further increase in gp39 expression by anti-CD3 Ab stimulation was markedly greater in lupus T cells. The pathogenic autoantibody-inducing ability of Th clones and splenic Th cells from lupus mice could be blocked in vitro by anti-gp39 Ab. Acceleration of lupus nephritis by the transfer of pathogenic autoantibody-inducing Th clones in vivo could also be completely blocked by anti-gp39 Ab. Surprisingly, a brief treatment of lupus mice with anti-gp39 Ab had a sustained beneficial effect on their spontaneous disease long after the Ab had been cleared from their systems. Only three injections of anti-gp39 Ab given to prenephritic lupus mice at 3 mo of age markedly delayed and reduced the incidence of lupus nephritis up to 12 mo of age by which time almost all the control mice had developed severe glomerulonephritis. Remarkably, pathogenic Th cells were left intact in these anti-gp39-treated mice but their B cells could not produce pathogenic autoantibodies even 9 mo after the therapy. Our studies suggest that blocking the interaction between gp39 on pathogenic Th cells and CD40 on lupus B cells at a crucial window of time delays the expansion autoimmune memory B cells resulting in long-term therapeutic benefits.