Merkenschlager Julia, Pyo Andrew G T, Silva Santos Gabriela S, Schaefer-Babajew Dennis, Cipolla Melissa, Hartweger Harald, Gitlin Alexander D, Wingreen Ned S, Nussenzweig Michel C
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA.
Laboratory of Lymphocyte Collaboration and Competition, Harvard Medical School, Boston, MA, USA.
Nature. 2025 May;641(8062):495-502. doi: 10.1038/s41586-025-08728-2. Epub 2025 Mar 19.
Germinal centres are specialized microenvironments where B cells undergo affinity maturation. B cells expressing antibodies whose affinity is improved by somatic hypermutation are selected for expansion by limiting numbers of T follicular helper cells. Cell division is accompanied by mutation of the immunoglobulin genes, at what is believed to be a fixed rate of around 1 × 10 per base pair per cell division. As mutagenesis is random, the probability of acquiring deleterious mutations outweighs the probability of acquiring affinity-enhancing mutations. This effect might be heightened, and even become counterproductive, in B cells that express high-affinity antibodies and undergo the greatest number of cell divisions. Here we experimentally examine a theoretical model that explains how affinity maturation could be optimized by varying the rate of somatic hypermutation such that cells that express higher-affinity antibodies divide more but mutate less per division. Data obtained from mice immunized with SARS-CoV-2 vaccines or a model antigen align with the theoretical model and show that cells producing high-affinity antibodies shorten the G0/G1 phases of the cell cycle and reduce their mutation rates. We propose that these mechanisms safeguard high-affinity B cell lineages and enhance the outcomes of antibody affinity maturation.
生发中心是B细胞进行亲和力成熟的特殊微环境。表达通过体细胞超突变提高亲和力的抗体的B细胞，会被数量有限的滤泡辅助性T细胞选择进行扩增。细胞分裂伴随着免疫球蛋白基因的突变，据信每个细胞分裂时每碱基对的突变率约为1×10⁻⁵。由于诱变是随机的，获得有害突变的概率超过获得亲和力增强突变的概率。在表达高亲和力抗体并经历最多细胞分裂次数的B细胞中，这种影响可能会加剧，甚至适得其反。在这里，我们通过实验检验了一个理论模型，该模型解释了如何通过改变体细胞超突变率来优化亲和力成熟，使得表达更高亲和力抗体的细胞分裂更多但每次分裂的突变更少。从小鼠接种SARS-CoV-2疫苗或模型抗原后获得的数据与该理论模型相符，并表明产生高亲和力抗体的细胞缩短了细胞周期的G0/G1期并降低了它们的突变率。我们提出，这些机制保护了高亲和力B细胞谱系并提高了抗体亲和力成熟的结果。
