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Dynamic regulation of somatic hypermutation in germinal centers enables rapid B cell clonal expansion without loss of affinity

ABSTRACT: In the course of antibody affinity maturation, germinal center (GC) B cells mutate their immunoglobulin (Ig) heavy and light chain genes in a process known as somatic hypermutation (SHM). Panels of mutant B cells with different binding affinities for antigen are then selected in Darwinian fashion, leading to a progressive increase in affinity among the population. As with any Darwinian process, rare gain-of-fitness mutations must be identified while common loss-of-fitness mutations are avoided. Progressive acquisition of mutations therefore poses a risk during large proliferative bursts, when GC B cells go through several cell cycles in the absence of affinity-based selection. Using a combination of in vivo mouse experiments and mathematical modeling, 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 during such bursts do not deviate from their ancestral genotype. Intravital imaging and image-based cell sorting of a new CyclinE(A)/cyclin-dependent kinase 2 (CDK2) reporter mouse strain showed that B cells 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 largely delay SHM until the G0-like phase that follows their final round of division in the DZ, thus maintaining affinity as they clonally expand in the absence of selection.

ORGANISM(S): Mus musculus

PROVIDER: GSE285185 | GEO | 2025/03/17

REPOSITORIES: GEO

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Project description:The germinal center response or reaction (GCR) is a hallmark event of adaptive humoral immunity. Unfolding in the B cell follicles of the secondary lymph organs, a GC culminates in the production of high-affinity antibody-secreting plasma cells along with memory B cells. By interacting with follicular dendritic cells (FDC) and T follicular helper (Tfh) cells, GC B cells exhibit complex spatiotemporal dynamics. Driving the B cell dynamics are the intracellular signal transduction and gene regulatory network that responds to cell surface signaling molecules, cytokines, and chemokines. As our knowledge of the GC continues to expand in depth and in scope, mathematical modeling has become an important tool to help disentangle the intricacy of the GCR and inform novel mechanistic and clinical insights. While the GC has been modeled at different granularities, a multiscale spatial simulation framework – integrating molecular, cellular, and tissue-level responses – is still rare. Here, we report our recent progress toward this end with a hybrid stochastic GC framework developed on the Cellular Potts Model-based CompuCell3D platform. Tellurium is used to simulate the B cell intracellular molecular network comprising NF-κB, FOXO1, MYC, AP4, CXCR4, and BLIMP1 that responds to B cell receptor (BCR) and CD40-mediated signaling. The molecular outputs of the network drive the spatiotemporal behaviors of B cells, including cyclic migration between the dark zone (DZ) and light zone (LZ) via chemotaxis; clonal proliferative bursts, somatic hypermutation, and DNA damage-induced apoptosis in the DZ; and positive selection, apoptosis via a death timer, and emergence of plasma cells in the LZ. Our simulations are able to recapitulate key molecular, cellular, and morphological GC events including B cell population growth, affinity maturation, and clonal dominance. This novel modeling framework provides an open-source, customizable, and multiscale virtual GC simulation platform that enables qualitative and quantitative in silico investigations of a range of mechanic and applied research questions on the adaptive humoral immune response in future.

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Dynamic regulation of somatic hypermutation in germinal centers enables rapid B cell clonal expansion without loss of affinity

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