Selective Targeting of B Cells with Agonistic Anti-CD40 Is an Efficacious Strategy for the Generation of Induced Regulatory T2-Like B Cells and for the Suppression of Lupus in MRL/lpr Mice

We have previously reported that IL-10(+) regulatory B cells, known to play an important role in controlling autoimmunity and inflammatory disorders, are contained within the transitional 2 immature (T2) B cell pool (T2 Bregs). Therapeutic strategies facilitating their enrichment or enhancing their suppressive activity are highly attractive. In this study, we report that agonistic anti-CD40 specifically targets T2 B cells and enriches Bregs upon short-term in vitro culture. Although transfer of unmanipulated T2 B cells, isolated from mice with established lupus, failed to confer protection to diseased mice, transfer of in vitro anti-CD40-generated T2 B cells (T2-like-Bregs) significantly improved renal disease and survival by an IL-10-dependent mechanism. T2-like-Bregs readily accumulated in the spleen after transfer, suppressed Th1 responses, induced the differentiation of IL-10(+)CD4(+)T cells, and conveyed a regulatory effect to CD4(+)T cells. In addition, in vivo administration of agonistic anti-CD40, currently on trial for the treatment of cancer, halted and reversed established lupus. Taken together, our results suggest a novel cellular approach for the amelioration of experimental lupus. The Journal of Immunology, 2009, 182: 3492-3502.