title: CD43-, but not CD43+, IL-10-producing CD1dhiCD5+ B cells suppress type 1 immune responses during Chlamydia muridarum genital tract infection.
abstract: Regulatory B (Breg) cells are known to modulate immune responses through predominantly interleukin-10 (IL-10)-dependent mechanisms and can be hypothetically divided into innate and adaptive subsets based on the nature of their activating signals. However, the specific role of different Breg subsets in modulating immune responses remains ambiguous. Here we have shown that Chlamydia induces IL-10-producing splenic B-cell populations consisting of CD43(+) and CD43(-) subsets of IgM(hi)IgD(lo) innate-like B (ILB) cells in vitro. While CD43(+)IL-10-producing B cells displayed innate type features and were readily induced by Chlamydia via Toll-like-receptor (TLR) signaling, CD43(-)IL-10-producing B cells required additional B-cell activating factor (BAFF)-mediated signals from dendritic cells (DCs) for their differentiation and activation, thereby classifying them as adaptive type Bregs. Importantly, CD43(-), but not CD43(+), IL-10-producing ILB cells displayed bona fide Breg activity by potently suppressing interferon-γ (IFN-γ) production in vitro in an IL-10-dependent manner. Furthermore, a novel CD43(-)CD1d(hi)CD5(+) IL-10-producing Breg population was predominantly induced by Chlamydia genital infection in vivo. Correspondingly, mixed bone marrow chimeric mice with B-cell-specific IL-10 deficiency exhibited significantly increased type 1 immune responses, decreased bacterial burden, and reduced oviduct pathology upon infection. Our data demonstrate for the first time a distinct role for CD43(-)CD1d(hi)CD5(+)-adaptive Bregs over CD43(+) innate counterparts in controlling mucosal responses against intracellular bacterial infection.
authors.affiliation: 1] Canadian Center for Vaccinology, Dalhousie University, Halifax, Nova Scotia, Canada [2] Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: J M
authors.initials: JM
authors.lastname: Moore-Connors
authors.affiliation: 1] Canadian Center for Vaccinology, Dalhousie University, Halifax, Nova Scotia, Canada [2] Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: J S
authors.initials: JS
authors.lastname: Marshall
authors.affiliation: 1] Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada [2] Faculty of Medicine, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada [3] IWK Health Centre, Halifax, Nova Scotia, Canada B3K 6R8.
authors.forename: A W
authors.initials: AW
authors.lastname: Stadnyk
authors.affiliation: 1] Canadian Center for Vaccinology, Dalhousie University, Halifax, Nova Scotia, Canada [2] Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada [3] Faculty of Medicine, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada [4] IWK Health Centre, Halifax, Nova Scotia, Canada B3K 6R8.
authors.forename: S A
authors.initials: SA
authors.lastname: Halperin
authors.affiliation: 1] Canadian Center for Vaccinology, Dalhousie University, Halifax, Nova Scotia, Canada [2] Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada [3] Faculty of Medicine, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada [4] IWK Health Centre, Halifax, Nova Scotia, Canada B3K 6R8.
authors.forename: J
authors.initials: J
authors.lastname: Wang
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D018949:Antigens, CD1 / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D060151:B-Lymphocytes, Regulatory / Q000276:immunology*; D058491:Bacterial Load; D018956:CD5 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002678:Chimera; D002690:Chlamydia Infections / Q000276:immunology*; D023502:Chlamydia muridarum / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005835:Genitalia / Q000276:immunology* / Q000382:microbiology; D007113:Immunity, Innate; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D051917:Leukosialin / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D018949:Antigens, CD1; D053265:B-Cell Activation Factor Receptor; D018956:CD5 Antigens; D007148:Immunoglobulin mu-Chains; D051917:Leukosialin; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016753:Interleukin-10