Interleukin-35 induces regulatory B cells that suppress autoimmune disease.

Abstract

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.

• Authors: 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
• Journal: Nature medicine (Nat Med) Vol. 20 Issue 6 Pg. 633-41 (Jun 2014) ISSN: 1546-170X [Electronic] United States
• PMID: 24743305 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• DNA Primers
• Interleukin-12 Receptor beta 2 Subunit
• Interleukins
• Recombinant Proteins
• interleukin-35, mouse
• Interleukin-10

Topics

• Adoptive Transfer (methods)
• Animals
• Autoimmune Diseases (drug therapy)
• B-Lymphocytes, Regulatory (metabolism)
• Blotting, Western
• Chromatin Immunoprecipitation
• DNA Primers (genetics)
• Genetic Engineering
• Immunoprecipitation
• Interleukin-10 (metabolism)
• Interleukin-12 Receptor beta 2 Subunit (genetics)
• Interleukins (administration & dosage, genetics, metabolism, pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Real-Time Polymerase Chain Reaction
• Recombinant Proteins (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Statistics, Nonparametric
• Uveitis (drug therapy)