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.
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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.
The authors declare no competing financial interests.
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Wang, R., Yu, C., Dambuza, I. et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med 20, 633–641 (2014). https://doi.org/10.1038/nm.3554
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