Interleukin-35 induces regulatory B cells that suppress autoimmune disease

Interleukin-10 (IL-10)-producing regulatory B (Bred cells suppress autoimmune disease, and increased numbers of B-reg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (T-reg) cells. The mechanisms mediating the induction and development of B-reg cells remain unclear. Here we show that IL-35 induces B-reg cells and promotes their conversion to a B-reg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12R beta 2 KO mice) produced less B-reg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of B-reg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (T(H)17) and T(H)1 cells while promoting T-reg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12R beta 2 and IL-27R alpha subunits. As IL-35 also induced the conversion of human B cells into B-reg cells, these findings suggest that IL-35 may be used to induce autologous B-reg and IL-35(+) B-reg cells and treat autoimmune and inflammatory disease.