title: 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.affiliation: 1] Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland, USA. [2] Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Ren-Xi
authors.initials: RX
authors.lastname: Wang
authors.affiliation: Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Cheng-Rong
authors.initials: CR
authors.lastname: Yu
authors.affiliation: Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Ivy M
authors.initials: IM
authors.lastname: Dambuza
authors.affiliation: Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Rashid M
authors.initials: RM
authors.lastname: Mahdi
authors.affiliation: Ophthalmic Genetics and Visual Functions Branch, NEI, NIH, Bethesda, Maryland, USA.
authors.forename: Monika B
authors.initials: MB
authors.lastname: Dolinska
authors.affiliation: Ophthalmic Genetics and Visual Functions Branch, NEI, NIH, Bethesda, Maryland, USA.
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Sergeev
authors.affiliation: Protein Expression Laboratory, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Wingfield
authors.affiliation: Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Sung-Hye
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Egwuagu
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D060151:B-Lymphocytes, Regulatory / Q000378:metabolism*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D005818:Genetic Engineering; D047468:Immunoprecipitation; D016753:Interleukin-10 / Q000378:metabolism; D053712:Interleukin-12 Receptor beta 2 Subunit / Q000235:genetics; D007378:Interleukins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014605:Uveitis / Q000188:drug therapy*
chemical_list: D017931:DNA Primers; D053712:Interleukin-12 Receptor beta 2 Subunit; D007378:Interleukins; D011994:Recombinant Proteins; C569375:interleukin-35, mouse; D016753:Interleukin-10
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