2020年10月28日出版的《自然》杂志在线发表了美国洛克菲勒大学Gabriel D. Victora和Daniel Mucida课题组合作的最新研究成果。他们揭示了肠道生发中心B细胞选择的可调动力学。

通过结合多色“Brainbow”细胞命运图谱和对单个细胞免疫球蛋白的基因测序数据，研究人员发现尽管生发中心B细胞快速更新，但在稳态无特定病原体（SPF）小鼠5-10％的肠道相关生发中心中包含主导性 “winner”B细胞克隆。与它们未突变的前体相比，由这些B细胞克隆产生的单克隆抗体具有更强的与共生细菌结合能力，这与抗原驱动的选择一致。

无菌小鼠中高度选择性肠道相关生发中心的频率显著高于SPF小鼠，并且无菌小鼠生发中心中的winnerB细胞与在多个其他个体中发现的``公共''克隆型相似，这表明即使在没有微生物群的情况下仍存在频繁的B细胞抗原受体选择。用既定微生物群落（Oligo-MM12）对无菌小鼠进行定殖并不能消除与细菌相关的克隆型，但会诱发伴随抗原诱导选择的共生特异性B细胞反应。因此，可以在稳态肠道相关生发中心进行B细胞的阳性选择，其选择速率范围可通过调节微生物群的存在和组成来实现。

据了解，生发中心是B细胞产生对各种抗原具有高亲和力抗体的结构，通常在感染或免疫后的淋巴器官中短暂形成。然而，在肠道淋巴器官中生发中心长期存在。这些与肠道相关的生发中心可以提供针对肠道感染和免疫的靶向抗体反应。但是，在稳态情况下，面对肠道中慢性多样性抗原的刺激是否进行B细胞选择和高亲和力抗体的成熟尚不清楚。

附：英文原文

Title: Tunable dynamics of B cell selection in gut germinal centres

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

Issue&Volume: 2020-10-28

Abstract: 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 immunization1. 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 clear2,3,4,5,6,7,8. 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.

DOI: 10.1038/s41586-020-2865-9

Source: https://www.nature.com/articles/s41586-020-2865-9