Regulated somatic hypermutation enhances antibody affinity maturation

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Rockefeller University; Harvard University; Harvard Medical School; Princeton University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Princeton University; Princeton University; Howard Hughes Medical Institute; Rockefeller University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3129
• DOI: 10.1038/s41586-025-08728-2
• 发表日期: 2025-05-08
• 关键词: induced cytidine deaminase; class switch recombination; germinal center selection; cell-cycle; aid; mechanisms; expression; DYNAMICS; cloning; FAMILY

摘要

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 x 10-3 per base pair per cell division1. 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 divisions2. 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.