Interleukin-35 induces regulatory B cells that suppress autoimmune disease

Ren-Xi Wang, Cheng-Rong Yu, Ivy M. Dambuza, Rashid M. Mahdi, Monika B. Dolinska, Yuri V. Sergeev, Paul T. Wingfield, Sung-Hye Kim, Charles E. Egwuagu (Corresponding Author)

Research output: Contribution to journalArticlepeer-review

531 Citations (Scopus)


Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg 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 Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg 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 Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.

Original languageEnglish
Pages (from-to)633-641
Number of pages9
JournalNature Medicine
Issue number6
Early online date17 Apr 2014
Publication statusPublished - Jun 2014


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