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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