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)

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581 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

Bibliographical note

The Intramural Research Programs of the NEI and NIH provided funding for this research. We thank H. Young (National Cancer Institute, NIH) and R.R. Caspi and C.-C. Chan (NEI, NIH) for critical reading of the manuscript. We also thank C.-C. Chan for expert analyses of Fundus images and histology sections. In addition, we thank A. O'Hara and C.A. Hunter (University of Pennsylvania) for providing IL-27Rα KO B cells and R. Villasmil (NEI/NIH FLOW Cytometry Core facility) for cell sorting and FACS analysis.


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