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Regulated somatic hypermutation enhances antibody affinity maturation

Author

Listed:
  • Julia Merkenschlager

    (The Rockefeller University
    Harvard Medical School)

  • 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
    Memorial Sloan Kettering Cancer Center)

  • Ned S. Wingreen

    (Princeton University
    Princeton University)

  • Michel C. Nussenzweig

    (The Rockefeller University
    The Rockefeller University)

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.

Suggested Citation

  • Julia Merkenschlager & Andrew G. T. Pyo & Gabriela S. Silva Santos & Dennis Schaefer-Babajew & Melissa Cipolla & Harald Hartweger & Alexander D. Gitlin & Ned S. Wingreen & Michel C. Nussenzweig, 2025. "Regulated somatic hypermutation enhances antibody affinity maturation," Nature, Nature, vol. 641(8062), pages 495-502, May.
  • Handle: RePEc:nat:nature:v:641:y:2025:i:8062:d:10.1038_s41586-025-08728-2
    DOI: 10.1038/s41586-025-08728-2
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