Interleukin-35 Induces Regulatory B Cells that Suppress CNS Autoimmune Disease

Interleukin 10-producing regulatory B-cells (Breg-cells) suppress autoimmune diseases while aberrant elevation of Breg-cells prevents sterilizing immunity, promotes carcinogenesis and cancer metastasis by converting resting CD4(+) T-cells to regulatory T-cells (Tregs). It is therefore of interest to discover factors that induce Breg-cells. Here we show that IL-35 induces Breg-cells in-vivo and promotes their conversion to a unique Breg subset that produces IL-35 (IL-35(+)Breg). Treatment of mice with IL-35 conferred protection from uveitis and mice lacking IL-35 or defective in IL-35-signaling produced less Breg-cells and developed severe uveitis. Ex-vivo generated Breg-cells also suppressed uveitis by inhibiting pathogenic Th17/Th1 while promoting Tregs expansion. We further show that IL-35 induced the conversion of human B-cells into Breg-cells and suppressed uveitis by activating STAT1/STAT3 through IL-35-Receptor comprising IL-12Rβ2/IL-27Rα subunits. Discovery that IL-35 converts human B-cells into Breg-cells, allows ex-vivo production of autologous Breg-cells for immunotherapy and investigating Breg/IL-35(+)Breg cells roles in autoimmune diseases and cancer.