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-Faslpr/lpr mice. BAFF-induced IL-35–producing B cells were mainly from the marginal zone B-cell subset and exhibited a CD5+CD1dhiFcγRIIbhi 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+CD1dhiFcγRIIbhi B cells in MRL-Faslpr/lpr mice. We showed that BAFF could induce IL-35 production by a unique CD5+CD1dhiFcγRIIbhi regulatory B-cell subset mainly through TACI activation in lupus, providing an advanced understanding of the regulatory effect of BAFF in autoimmune diseases.
Zhang, Y., Li, J., Zhou, N., Zhang, Y., Wu, M., Xu, J., … Tao, J. (2017). The Unknown Aspect of BAFF: Inducing IL-35 Production by a CD5+CD1dhiFcγRIIbhi Regulatory B-Cell Subset in Lupus. Journal of Investigative Dermatology, 137(12), 2532–2543. https://doi.org/10.1016/j.jid.2017.07.843