Moore-Connors J M, Kim H S, Marshall J S, Stadnyk A W, Halperin S A, Wang J
1] Canadian Center for Vaccinology, Dalhousie University, Halifax, Nova Scotia, Canada [2] Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Mucosal Immunol. 2015 Jan;8(1):94-106. doi: 10.1038/mi.2014.45. Epub 2014 Jun 18.
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.
调节性B（Breg）细胞已知主要通过白介素10（IL-10）依赖机制调节免疫反应，并且基于其激活信号的性质，理论上可分为先天型和适应性亚群。然而，不同Breg亚群在调节免疫反应中的具体作用仍不明确。在此，我们表明衣原体在体外诱导产生IL-10的脾脏B细胞群体，该群体由IgM(hi)IgD(lo)先天样B（ILB）细胞的CD43(+)和CD43(-)亚群组成。虽然产生IL-10的CD43(+) B细胞表现出先天型特征，并容易被衣原体通过Toll样受体（TLR）信号诱导，但产生IL-10的CD43(-) B细胞需要来自树突状细胞（DC）的额外B细胞激活因子（BAFF）介导的信号来实现其分化和激活，因此将它们归类为适应性Breg。重要的是，产生IL-10的ILB细胞中，CD43(-)而非CD43(+)细胞通过以IL-10依赖方式在体外有效抑制干扰素-γ（IFN-γ）产生，表现出真正的Breg活性。此外，一种新的产生IL-10的CD43(-)CD1d(hi)CD5(+) Breg群体在体内主要由衣原体生殖道感染诱导产生。相应地，具有B细胞特异性IL-10缺陷的混合骨髓嵌合小鼠在感染后表现出1型免疫反应显著增加、细菌负荷降低以及输卵管病理变化减轻。我们的数据首次证明，在控制针对细胞内细菌感染的黏膜反应方面，CD43(-)CD1d(hi)CD5(+)适应性Breg相对于CD43(+)先天型Breg具有独特作用。
