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BCR selection and affinity maturation in Peyer's patch germinal centres

机译：BCR选择和亲和力成熟在Peyer的补丁发芽中心

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摘要

Abstract The antigen-binding variable regions of the B cell receptor (BCR) and of antibodies are encoded by exons that are assembled in developing B cells by V(D)J recombination1. The BCR repertoires of primary B cells are vast owing to mechanisms that create diversity at the junctions of V(D)J gene segments that contribute to complementarity-determining region 3 (CDR3), the region that binds antigen1. Primary B cells undergo antigen-driven BCR affinity maturation through somatic hypermutation and cellular selection in germinal centres (GCs)2,3. Although most GCs are transient3, those in intestinal Peyer’s patches (PPs)—which depend on the gut microbiota—are chronic4, and little is known about their BCR repertoires or patterns of somatic hypermutation. Here, using a high-throughput assay that analyses both V(D)J segment usage and somatic hypermutation profiles, we elucidate physiological BCR repertoires in mouse PP GCs. PP GCs from different mice expand public BCR clonotypes (clonotypes that are shared between many mice) that often have canonical CDR3s in the immunoglobulin heavy chain that, owing to junctional biases during V(D)J recombination, appear much more frequently than predicted in naive B cell repertoires. Some public clonotypes are dependent on the gut microbiota and encode antibodies that are reactive to bacterial glycans, whereas others are independent of gut bacteria. Transfer of faeces from specific-pathogen-free mice to germ-free mice restored germ-dependent clonotypes, directly implicating BCR selection. We identified somatic hypermutations that were recurrently selected in such public clonotypes, indicating that affinity maturation occurs in mouse PP GCs under homeostatic conditions. Thus, persistent gut antigens select recurrent BCR clonotypes to seed chronic PP GC responses.
机译：摘要B细胞受体（BCR）和抗体的抗原结合可变区由显影B细胞通过V（D）J Refombination1组装的外显子编码。主要B细胞的BCR曲目由于在助升性确定区域3（CDR3）的V（D）J基因段的结合的v（d）j基因段的结合，该机制而产生多样性。初级B细胞通过生发中心（GCS）2,3中的体细胞增强和细胞选择进行抗原驱动的BCR亲和力成熟。尽管大多数GCS是瞬间3，但是在肠道Peyer的补丁（PPS）中的那些 - 依赖于肠道微生物A-慢性4，并且关于它们的BCR曲目或体细胞高压模式几乎不少。这里，使用分析V（d）j段使用和体细胞增强型谱的高通量测定，我们在小鼠PP GCS中阐明生理BCR曲目。来自不同小鼠的PP GCS扩展公共BCR Clonotypes（在许多小鼠之间共同共享的Clonotypes），其在免疫球蛋白重链中通常具有规范CDR3S，因为在V（d）J重组期间的结偏差，比在Naive中的预测更频繁地看出B细胞曲目。一些公共克洛尼型依赖于肠道微生物群和对细菌聚糖反应的编码抗体，而其他则与细菌菌有关。将粪便从无菌小鼠转移到无菌小鼠恢复的胚芽依赖性克隆型，直接暗示BCR选择。我们鉴定了在这种公共克隆型中常常选择的体细胞高压，表明亲和力成熟在稳态条件下的小鼠PP GCS中发生。因此，持续的肠道抗原选择经复制的BCR Clonotypes对种子慢性PP GC反应。

著录项

  • 来源
    《Nature》 |2020年第7812期|421-425|共5页
  • 作者

    Huan Chen; Yuxiang Zhang; Adam Yongxin Ye; Zhou Du; Mo Xu; Cheng-Sheng Lee; Joyce K. Hwang; Nia Kyritsis; Zhaoqing Ba; Donna Neuberg; Dan R. Littman; Frederick W. Alt;

  • 作者单位

    Boston Children’s Hospital|Harvard Medical School|Boston Children’s Hospital;

    Boston Children’s Hospital|Harvard Medical School|Boston Children’s Hospital;

    Boston Children’s Hospital|Harvard Medical School|Boston Children’s Hospital;

    Boston Children’s Hospital|Harvard Medical School|Boston Children’s Hospital;

    New York University School of Medicine|New York University School of Medicine;

    Boston Children’s Hospital|Harvard Medical School|Boston Children’s Hospital;

    Boston Children’s Hospital|Harvard Medical School|Boston Children’s Hospital;

    Boston Children’s Hospital|Harvard Medical School|Boston Children’s Hospital;

    Boston Children’s Hospital|Harvard Medical School|Boston Children’s Hospital;

    Dana-Farber Cancer Institute;

    New York University School of Medicine|New York University School of Medicine;

    Boston Children’s Hospital|Harvard Medical School|Boston Children’s Hospital;

  • 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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