研究揭示腸道生發中心B細胞選擇的可調動力學
作者：
小柯機器人發布時間：2020/10/31 20:02:34
2020年10月28日出版的《自然》雜誌在線發表了美國洛克菲勒大學Gabriel D. Victora和Daniel Mucida課題組合作的最新研究成果。他們揭示了腸道生發中心B細胞選擇的可調動力學。
通過結合多色「Brainbow」細胞命運圖譜和對單個細胞免疫球蛋白的基因測序數據，研究人員發現儘管生發中心B細胞快速更新，但在穩態無特定病原體（SPF）小鼠5-10％的腸道相關生發中心中包含主導性 「winner」B細胞克隆。與它們未突變的前體相比，由這些B細胞克隆產生的單克隆抗體具有更強的與共生細菌結合能力，這與抗原驅動的選擇一致。
無菌小鼠中高度選擇性腸道相關生發中心的頻率顯著高於SPF小鼠，並且無菌小鼠生發中心中的winnerB細胞與在多個其他個體中發現的``公共''克隆型相似，這表明即使在沒有微生物群的情況下仍存在頻繁的B細胞抗原受體選擇。用既定微生物群落（Oligo-MM12）對無菌小鼠進行定殖並不能消除與細菌相關的克隆型，但會誘發伴隨抗原誘導選擇的共生特異性B細胞反應。因此，可以在穩態腸道相關生發中心進行B細胞的陽性選擇，其選擇速率範圍可通過調節微生物群的存在和組成來實現。
據了解，生發中心是B細胞產生對各種抗原具有高親和力抗體的結構，通常在感染或免疫後的淋巴器官中短暫形成。然而，在腸道淋巴器官中生發中心長期存在。這些與腸道相關的生發中心可以提供針對腸道感染和免疫的靶向抗體反應。但是，在穩態情況下，面對腸道中慢性多樣性抗原的刺激是否進行B細胞選擇和高親和力抗體的成熟尚不清楚。
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