title: Induction and Differentiation of IL-10-Producing Regulatory B Cells from Healthy Blood Donors and Rheumatoid Arthritis Patients.
abstract: The most important feature of B cells is the production of Abs upon activation; additionally, B cells produce pro- and anti-inflammatory cytokines in response to certain stimuli. IL-10-producing B cells represent a major subset of regulatory B cells (Bregs) that suppress autoimmune and inflammatory responses. B cells play a crucial role in the development and maintenance of the chronic inflammatory autoimmune disease rheumatoid arthritis (RA); however, controversial data are available on IL-10- producing Bregs in RA. Our aim was to identify the optimal conditions that induce IL-10+Bregs and, furthermore, to shed light on the signaling pathways that are responsible for their expansion. The results show that dual stimulation by CpG and CD40L for 48 h is optimal for IL-10 induction, and this can be synergistically boosted by IL-21. We identified the CD19+CD27+memory B cell population as the major source of IL-10+Bregs. We detected significantly fewer CD19+CD27+IL-10+cells in RA patients compared with healthy controls, and these were functionally defective in suppressing IFN-γ production by CD4+T cells in coculture. IL-21 drastically increased the number of IL-10+Bregs within the CD19+CD27+and CD19+CD27-populations; furthermore, it induced the appearance of IL-10+Blimp-1+plasmablasts. Monitoring the phosphorylation of key signaling molecules revealed that activation of ERK, p38, and CREB is indispensable for the induction of IL-10 production, whereas phosphorylation of STAT3 further enhances IL-10 expression in human Bregs. We conclude that CREB and STAT3 are the key transcription factors responsible for the expansion and differentiation of human IL-10-producing Bregs.
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, 1117 Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bankó
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, 1117 Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Pozsgay
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, 1117 Hungary.
authors.forename: Dániel
authors.identifier: 0000-0002-9533-1624
authors.initials: D
authors.lastname: Szili
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, 1117 Hungary.
authors.forename: Mária
authors.identifier: 0000-0001-7620-2889
authors.initials: M
authors.lastname: Tóth
authors.affiliation: Buda Hospital of Hospitaller Brothers of St. John, Budapest, 1023 Hungary; and.
authors.forename: Tamás
authors.identifier: 0000-0002-7549-8291
authors.initials: T
authors.lastname: Gáti
authors.affiliation: Buda Hospital of Hospitaller Brothers of St. John, Budapest, 1023 Hungary; and.|Department of Rheumatology, 3rd Department of Internal Medicine, Semmelweis University, Budapest, 1023 Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Nagy
authors.affiliation: Buda Hospital of Hospitaller Brothers of St. John, Budapest, 1023 Hungary; and.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Rojkovich
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, 1117 Hungary; sarmayg@ttk.elte.hu.
authors.forename: Gabriella
authors.identifier: 0000-0002-3066-7768
authors.initials: G
authors.lastname: Sármay
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D060151:B-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D001782:Blood Donors; D023201:CD40 Ligand / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: C508609:IL10 protein, human; D009838:Oligodeoxyribonucleotides; D016753:Interleukin-10; D023201:CD40 Ligand