Interleukin-35 induces regulatory B cells that suppress autoimmune disease

Interleukin-10 (IL-10)-producing regulatory B ([B.sub.reg]) cells suppress autoimmune disease, and increased numbers of [B.sub.reg] cells prevent host defense to infection and promote tumor growth and metastasis by converting resting [CD4.sup.+] T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of [B.sub.reg] cells remain unclear. Here we show that IL-35 induces [B.sub.reg] cells and promotes their conversion to a [B.sub.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-12Rβ2 KO mice) produced less [B.sub.reg] cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of [B.sub.reg] cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 ([T.sub.H]17) and [T.sub.H]1 cells while promoting [T.sub.reg] cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into [B.sub.reg] cells, these findings suggest that IL-35 may be used to induce autologous [B.sub.reg] and [IL-35.sup.+] [B.sub.reg] cells and treat autoimmune and inflammatory disease.
B cell depletion is an effective therapy for a number of T cell-mediated autoimmune diseases, suggesting that B cells may contribute to autoimmunity (1-4). However, subsequent studies showed that the [...]