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祁海团队揭示高亲和力抗体筛选的新机制
2021-02-18 16:28

清华大学祁海研究团队揭示高亲和力抗体筛选的新机制。相关论文于2021年2月17日在线发表于国际学术期刊《自然》。

据研究人员介绍,抗体亲和力成熟取决于稀有B细胞克隆在生发中心(GC)的正向选择,这些B细胞克隆通过体细胞超突变获得更高亲和力的B细胞受体,向滤泡性辅助T(TFH)细胞呈递更多的抗原,因此获得更多的接触依赖性T细胞帮助。由于这些GC B细胞和TFH细胞在混乱的GC环境中无法保持持久的接触,因此尚不清楚有足够的T细胞帮助累积地集中在那些稀有克隆上。

研究人员表明,在刺激CD40后,GC B细胞上调趋化因子CCL22,并在较小程度上上调CCL17。通过将趋化因子受体CCR4结合到TFH细胞上,CCL22和CCL17可以从远处吸引多个辅助细胞,从而增加了产生帮助的机会。在GC反应期间,获得更高抗原结合亲和力的B细胞表达更高水平的CCL22,从而“突显”这些高亲和力的GC B细胞。TFH细胞的急性增加或阻断分别有助于快速增加或减少GC B细胞的CCL22表达。

因此,基于趋化因子的细胞间反应回路将单个B细胞最近获得的T细胞帮助量与其随后吸引更多帮助的能力联系起来。当在B细胞中敲除CCL22和CCL17时,GC能够形成,但B细胞不能有效地亲和成熟。当在同一反应中与野生型B细胞竞争时,缺乏CCL22和CCL17的B细胞获得的T细胞帮助维持GC参与或发展为骨髓浆细胞的帮助较少。通过揭示一种趋化因子介导的机制,其突出显示了亲和力提高的B细胞对TFH细胞的优先帮助,这项研究揭示了GC正向选择的时空调控原理。 

附:英文原文

Title: Affinity-coupled CCL22 promotes positive selection in germinal centres

Author: Bo Liu, Yihan Lin, Jiacong Yan, Jiacheng Yao, Dan Liu, Weiwei Ma, Jianbin Wang, Wanli Liu, Chengshuo Wang, Luo Zhang, Hai Qi

Issue&Volume: 2021-02-17

Abstract: Antibody affinity maturation depends on positive selection in germinal centres (GCs) of rare B cell clones that acquire higher-affinity B cell receptors via somatic hypermutation, present more antigen to follicular helper T (TFH) cells and, consequently, receive more contact-dependent T cell help1. As these GC B cells and TFH cells do not maintain long-lasting contacts in the chaotic GC environment2,3,4, it is unclear how sufficient T cell help is cumulatively focused onto those rare clones. Here we show that, upon stimulation of CD40, GC B cells upregulate the chemokine CCL22 and to a lesser extent CCL17. By engaging the chemokine receptor CCR4 on TFH cells, CCL22 and CCL17 can attract multiple helper cells from a distance, thus increasing the chance of productive help. During a GC response, B cells that acquire higher antigen-binding affinities express higher levels of CCL22, which in turn ‘highlight’ these high-affinity GC B cells. Acute increase or blockade of TFH cells helps to rapidly increase or decrease CCL22 expression by GC B cells, respectively. Therefore, a chemokine-based intercellular reaction circuit links the amount of T cell help that individual B cells have received recently to their subsequent ability to attract more help. When CCL22 and CCL17 are ablated in B cells, GCs form but B cells are not affinity-matured efficiently. When competing with wild-type B cells in the same reaction, B cells lacking CCL22 and CCL17 receive less T cell help to maintain GC participation or develop into bone-marrow plasma cells. By uncovering a chemokine-mediated mechanism that highlights affinity-improved B cells for preferential help from TFH cells, our study reveals a principle of spatiotemporal orchestration of GC positive selection.

DOI: 10.1038/s41586-021-03239-2

Source: https://www.nature.com/articles/s41586-021-03239-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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

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