美国波士顿儿童医院Frederick W. Alt研究组，近日阐明了Peyer斑块（PPs）生发中心（GCs）的B细胞受体（BCR）选择和亲和力成熟。2020年5月6日，《自然》发表了这项成果。
通过使用高通量分析（同时分析V（D）J片段使用情况和体细胞超突变谱），他们阐明了小鼠PP GC中的生理BCR组成。来自不同小鼠的PP GC扩展了公共BCR克隆型（许多小鼠之间共享的克隆型），它们通常在免疫球蛋白重链中具有经典的互补决定区域3（CDR3），由于V（D）J重组期间的连接偏好，其比预测的先天B细胞库出现的频繁的多。
一些公共克隆型依赖于肠道菌群并编码对细菌聚糖具有反应性的抗体，而另一些则不依赖于肠道细菌。粪便从无特定病原体的小鼠转移至无菌小鼠，能够回复细菌依赖性克隆型，直接暗示了BCR选择性。他们确定了在此类公共克隆型中反复选择的体细胞超突变，表明在稳态条件下，亲和力成熟在小鼠PP GC中发生。因此，持久性肠道抗原选择再生的BCR克隆型来启动慢性PP GC反应。
据了解，BCR和抗体的抗原结合可变区由外显子编码，这些外显子通过V（D）J重组在发育中的B细胞中组装。由于在V（D）J基因片段的连接处产生多样性的机制，原代B细胞的BCR类别非常丰富，而这些片段有助于CDR3形成，CDR3即与抗原结合的区域。原代B细胞经历抗原驱动的BCR亲和力成熟，是通过体细胞超突变和GCs中的细胞选择进行的。尽管大多数GC是短暂的，但肠道PPs（取决于肠道菌群）中的GC是慢性的，对其BCR组成部分或体细胞超突变模式了解甚少。
附：英文原文
Title: BCR selection and affinity maturation in Peyer’s patch germinal centres
Author: 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
Issue&Volume: 2020-05-06
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.
DOI: 10.1038/s41586-020-2262-4
Source: https://www.nature.com/articles/s41586-020-2262-4
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
