Transient silencing of hypermutation preserves B cell affinity during clonal bursting

Juhee Pae, Niklas Schwan, Bertrand Ottino-Loffler, William S. DeWitt, Amar Garg, Juliana Bortolatto, Ashni A. Vora, Jin-Jie Shen, Alvaro Hobbs, Tiago B. R. Castro, Luka Mesin, Frederick A. Matsen, Michael Meyer-Hermann and Gabriel D. Victora ()
Additional contact information
Juhee Pae: The Rockefeller University
Niklas Schwan: Helmholtz Center for Infection Research
Bertrand Ottino-Loffler: The Rockefeller University
William S. DeWitt: University of Washington
Amar Garg: Helmholtz Center for Infection Research
Juliana Bortolatto: The Rockefeller University
Ashni A. Vora: The Rockefeller University
Jin-Jie Shen: The Rockefeller University
Alvaro Hobbs: The Rockefeller University
Tiago B. R. Castro: The Rockefeller University
Luka Mesin: The Rockefeller University
Frederick A. Matsen: University of Washington
Michael Meyer-Hermann: Helmholtz Center for Infection Research
Gabriel D. Victora: The Rockefeller University

Nature, 2025, vol. 641, issue 8062, 486-494

Abstract: Abstract In the course of antibody affinity maturation, germinal centre (GC) B cells mutate their immunoglobulin heavy- and light-chain genes in a process known as somatic hypermutation (SHM)1–4. Panels of mutant B cells with different binding affinities for antigens are then selected in a Darwinian manner, which leads to a progressive increase in affinity among the population5. As with any Darwinian process, rare gain-of-fitness mutations must be identified and common loss-of-fitness mutations avoided6. Progressive acquisition of mutations therefore poses a risk during large proliferative bursts7, when GC B cells undergo several cell cycles in the absence of affinity-based selection8–13. Using a combination of in vivo mouse experiments and mathematical modelling, here we show that GCs achieve this balance by strongly suppressing SHM during clonal-burst-type expansion, so that a large fraction of the progeny generated by these bursts does not deviate from their ancestral genotype. Intravital imaging and image-based cell sorting of a mouse strain carrying a reporter of cyclin-dependent kinase 2 (CDK2) activity showed that B cells that are actively undergoing proliferative bursts lack the transient CDK2low ‘G0-like’ phase of the cell cycle in which SHM takes place. We propose a model in which inertially cycling B cells mostly delay SHM until the G0-like phase that follows their final round of division in the GC dark zone, thus maintaining affinity as they clonally expand in the absence of selection.

Date: 2025
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DOI: 10.1038/s41586-025-08687-8

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