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Tunable dynamics of B cell selection in gut germinal centres

机译：肠道生发中心中B细胞选择的可调动力学

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摘要

Antibody selection and maturation within B cells found in gut-associated germinal centres is stimulated by the gut microbiota, to a degree that depends on the presence and composition of the microbes.Germinal centres, the structures in which B cells evolve to produce antibodies with high affinity for various antigens, usually form transiently in lymphoid organs in response to infection or immunization. In lymphoid organs associated with the gut, however, germinal centres are chronically present. These gut-associated germinal centres can support targeted antibody responses to gut infections and immunization(1). But whether B cell selection and antibody affinity maturation take place in the face of the chronic and diverse antigenic stimulation characteristic of these structures under steady state is less clear(2-8). Here, by combining multicolour 'Brainbow' cell-fate mapping and sequencing of immunoglobulin genes from single cells, we find that 5-10% of gut-associated germinal centres from specific-pathogen-free (SPF) mice contain highly dominant 'winner' B cell clones at steady state, despite rapid turnover of germinal-centre B cells. Monoclonal antibodies derived from these clones show increased binding, compared with their unmutated precursors, to commensal bacteria, consistent with antigen-driven selection. The frequency of highly selected gut-associated germinal centres is markedly higher in germ-free than in SPF mice, and winner B cells in germ-free germinal centres are enriched in 'public' clonotypes found in multiple individuals, indicating strong selection of B cell antigen receptors even in the absence of microbiota. Colonization of germ-free mice with a defined microbial consortium (Oligo-MM12) does not eliminate germ-free-associated clonotypes, yet does induce a concomitant commensal-specific B cell response with the hallmarks of antigen-driven selection. Thus, positive selection of B cells can take place in steady-state gut-associated germinal centres, at a rate that is tunable over a wide range by the presence and composition of the microbiota.
机译：在肠道相关生发中心中发现的B细胞内的抗体选择和成熟由肠道微生物刺激到取决于微生物的存在和组成的程度。晶体中心，B细胞演化以产生高分子的结构对各种抗原的亲和力，通常在淋巴器官中瞬时形成，响应感染或免疫。然而，在与肠道相关的淋巴器官中，生发中心是长期存在的。这些肠道相关的生发中心可以支持针对肠道感染和免疫（1）的靶向抗体反应。但是在面对稳定状态下这些结构的慢性和不同抗原刺激特性的慢性和不同的抗原刺激特性，是否发生了B细胞选择和抗体亲和力。这里，通过组合多色的“脑袋”细胞 - 命运测绘和来自单细胞的免疫球蛋白基因的测序，发现来自无菌无菌（SPF）小鼠的5-10％的肠道相关生发中心含有高度优势的“获胜者” B细胞克隆处于稳态，尽管发红细胞中心B细胞的速度快。衍生自这些克隆的单克隆抗体显示出增加的结合，与其未传养的前体相比，与抗原驱动的选择一致的非抗体的细菌相比。高度选择的肠道相关生发中心的频率明显高于SPF小鼠，并且无菌生发中心中的冠军B细胞在多个人中发现的“公共”克隆型中富集，表明B细胞的强烈选择抗原受体甚至在没有微生物群的情况下。具有定义的微生物联原（oligo-MM12）的无菌小鼠的定植不会消除无菌相关的克隆型，但确实诱导了与抗原驱动选择的标志的伴随的特异性B细胞响应。因此，B细胞的阳性选择可以在稳态肠道相关的生发中心中进行，其速率通过微生物群的存在和组成在很宽的范围内进行调谐。

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  • 来源
    《Nature》 |2020年第7837期|321-326|共6页
  • 作者

    Nowosad Carla R.; Mesin Luka; Castro Tiago B. R.; Wichmann Christopher; Donaldson Gregory P.; Araki Tatsuya; Schiepers Arien; Lockhart Ainsley A. K.; Bilate Angelina M.; Mucida Daniel; Victora Gabriel D.;

  • 作者单位

    Rockefeller Univ Lab Lymphocyte Dynam 1230 York Ave New York NY 10021 USA|Rockefeller Univ Lab Mucosal Immunol 1230 York Ave New York NY 10021 USA;

    Rockefeller Univ Lab Lymphocyte Dynam 1230 York Ave New York NY 10021 USA;

    Rockefeller Univ Lab Lymphocyte Dynam 1230 York Ave New York NY 10021 USA|Rockefeller Univ Lab Mucosal Immunol 1230 York Ave New York NY 10021 USA;

    Rockefeller Univ Lab Mucosal Immunol 1230 York Ave New York NY 10021 USA|Univ Med Ctr Rostock Dept Pediat Mucosal Immunol Grp Rostock Germany;

    Rockefeller Univ Lab Mucosal Immunol 1230 York Ave New York NY 10021 USA;

    Rockefeller Univ Lab Lymphocyte Dynam 1230 York Ave New York NY 10021 USA;

    Rockefeller Univ Lab Lymphocyte Dynam 1230 York Ave New York NY 10021 USA;

    Rockefeller Univ Lab Mucosal Immunol 1230 York Ave New York NY 10021 USA;

    Rockefeller Univ Lab Mucosal Immunol 1230 York Ave New York NY 10021 USA;

    Rockefeller Univ Lab Mucosal Immunol 1230 York Ave New York NY 10021 USA;

    Rockefeller Univ Lab Lymphocyte Dynam 1230 York Ave New York NY 10021 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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