洛克菲勒大学Victora, Gabriel D.团队取得一项新突破。他们报道了在克隆破裂期间，超突变的短暂沉默保留了B细胞的亲和力。该项研究成果发表在2025年3月19日出版的《自然》上。

通过结合体内motheme实验和数学模型，课题组发现GCs通过在克隆爆发型扩增过程中强烈抑制SHM来实现这种平衡，因此这些爆发产生的大部分后代不会偏离其祖先的基因型。一种携带细胞周期蛋白依赖性激酶2 （CDK2）活性报告基因的motheme菌株的活体成像和基于图像的细胞分选显示，积极经历增殖爆发的B细胞缺乏发生SHM的细胞周期的瞬时CDK2low“G0样”期。该研究团队提出了一个模型，在这个模型中，惯性循环的B细胞大多将SHM延迟到GC暗区最后一轮分裂后的G0样期，它们在没有选择的情况下克隆扩张时保持亲和力。

据介绍，在抗体亲和成熟过程中，生发中心（GC） B细胞在称为体细胞超突变（SHM）的过程中突变其免疫球蛋白重链和轻链基因。然后以达尔文的方式选择具有不同抗原结合亲和力的突变B细胞组，这导致群体之间的亲和力逐渐增加。与任何达尔文过程一样，罕见的适应性突变必须被识别出来，而常见的适应性突变必须被避免。因此，当GC B细胞在缺乏亲和选择的情况下经历几个细胞周期时，突变的渐进式获取在大规模增殖爆发中存在风险。

附：英文原文

Title: Transient silencing of hypermutation preserves B cell affinity during clonal bursting

Author: Pae, Juhee, Schwan, Niklas, Ottino-Loffler, Bertrand, DeWitt, William S., Garg, Amar, Bortolatto, Juliana, Vora, Ashni A., Shen, Jin-Jie, Hobbs, Alvaro, Castro, Tiago B. R., Mesin, Luka, Matsen, Frederick A., Meyer-Hermann, Michael, Victora, Gabriel D.

Issue&Volume: 2025-03-19

Abstract: In the course of antibody affinity maturation, germinal centre (GC) B cells mutate their immunoglobulin heavy- and light-chain genes in a process known as somatic hypermutation (SHM). Panels of mutant B cells with different binding affinities for antigens are then selected in a Darwinian manner, which leads to a progressive increase in affinity among the population. As with any Darwinian process, rare gain-of-fitness mutations must be identified and common loss-of-fitness mutations avoided. Progressive acquisition of mutations therefore poses a risk during large proliferative bursts, when GC B cells undergo several cell cycles in the absence of affinity-based selection. Using a combination of in vivo mouse experiments and mathematical modelling, here we show that GCs achieve this balance by strongly suppressing SHM during clonal-burst-type expansion, so that a large fraction of the progeny generated by these bursts does not deviate from their ancestral genotype. Intravital imaging and image-based cell sorting of a mouse strain carrying a reporter of cyclin-dependent kinase 2 (CDK2) activity showed that B cells that are actively undergoing proliferative bursts lack the transient CDK2low ‘G0-like’ phase of the cell cycle in which SHM takes place. We propose a model in which inertially cycling B cells mostly delay SHM until the G0-like phase that follows their final round of division in the GC dark zone, thus maintaining affinity as they clonally expand in the absence of selection.

DOI: 10.1038/s41586-025-08687-8

Source: https://www.nature.com/articles/s41586-025-08687-8