Regulated somatic hypermutation enhances antibody affinity maturation

Julia Merkenschlager (), Andrew G. T. Pyo, Gabriela S. Silva Santos, Dennis Schaefer-Babajew, Melissa Cipolla, Harald Hartweger, Alexander D. Gitlin, Ned S. Wingreen () and Michel C. Nussenzweig ()
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Julia Merkenschlager: The Rockefeller University
Andrew G. T. Pyo: Princeton University
Gabriela S. Silva Santos: The Rockefeller University
Dennis Schaefer-Babajew: The Rockefeller University
Melissa Cipolla: The Rockefeller University
Harald Hartweger: The Rockefeller University
Alexander D. Gitlin: Memorial Sloan Kettering Cancer Center
Ned S. Wingreen: Princeton University
Michel C. Nussenzweig: The Rockefeller University

Nature, 2025, vol. 641, issue 8062, 495-502

Abstract: Abstract 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 × 10−3 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.

Date: 2025
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DOI: 10.1038/s41586-025-08728-2

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