The Unknown Aspect of BAFF: Inducing IL-35 Production by a CD5+CD1dhiFcγRIIbhi Regulatory B-Cell Subset in Lupus

IL-35 is a critical immunosuppressive cytokine that plays an important role in various autoimmune diseases. The purpose of this study was to determine whether BAFF, a key pathogenic factor in systemic lupus erythematosus, also a dichotomous regulator for B-cell immune responses, has an effect on IL-35-producing regulatory B cells and their underlying mechanisms in lupus. We found that exogenous BAFF could induce IL-35 production by splenic B cells from MRL-Fas^lpr/lpr mice. BAFF-induced IL-35-producing B cells were mainly from the marginal zone B-cell subset and exhibited a CD5⁺CD1d^hiFcγRIIb^hi phenotype. These IL-35-producing regulatory B-cell subsets exhibited regulatory effects on both CD4⁺CD25^- T cells and CD4⁺CD25⁺ regulatory T cells. We further identified that BAFF-TACI interaction could induce the production of IL-35 through the classical NF-κB1 pathway. In vivo study also showed that BAFF could facilitate IL-35 secretion in marginal zone B cells, whereas anti-BAFF treatment could decrease the frequency of IL-35-producing CD5⁺CD1d^hiFcγRIIb^hi B cells in MRL-Fas^lpr/lpr mice. We showed that BAFF could induce IL-35 production by a unique CD5⁺CD1d^hiFcγRIIb^hi regulatory B-cell subset mainly through TACI activation in lupus, providing an advanced understanding of the regulatory effect of BAFF in autoimmune diseases.