Dynamic regulation of somatic hypermutation in germinal centers enables rapid B cell clonal expansion without loss of affinity
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ABSTRACT:
PROVIDER: PRJNA1201770 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31802914_1.fastq.gz | Fastqsanger.gz | |||
| SRR31802914_2.fastq.gz | Fastqsanger.gz | |||
| SRR31802915_1.fastq.gz | Fastqsanger.gz | |||
| SRR31802915_2.fastq.gz | Fastqsanger.gz | |||
| SRR31802916_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2025-03-17 | GSE285185 | GEO
Project description:Germinal centers (GCs) are microenvironments where B cells undergo affinity maturation through somatic hypermutation (SHM) and selection by T follicular helper (TFH) cells. While SHM introduces mutations at a fixed rate (~1x10⁻³ per base pair per division), most mutations are deleterious, particularly in high-affinity B cells undergoing many divisions. This study tests a theoretical model suggesting that high-affinity B cells optimize maturation by dividing more but mutating less per division. Data from mice immunized with SARS-CoV-2 or a model antigen support the model, showing that high-affinity B cells shorten their G0/G1 phases and reduce mutation rates, safeguarding their lineages and improving affinity maturation outcomes.
2025-01-27 | GSE287123 | GEO
Project description:Long primed germinal centers with enduring affinity maturation and clonal migration
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Project description:Germinal centers (GCs) are the engines of antibody evolution. Using HIV Env protein immunogen priming in rhesus monkeys (RM) followed by a long period without further immunization, we demonstrate GC B cells (BGC) lasted at least 6 months. A 186-fold BGC cell increase was present by week 10 compared to a conventional immunization. Single cell transcriptional profiling revealed both light and dark zone GC states were sustained. Antibody somatic hypermutation (SHM) of BGC cells continued to accumulate throughout the 29-week priming period, with evidence of selective pressure. Env-binding BGC cells were still 49-fold above baseline at 29 weeks, suggesting they could be active for even longer periods of time. High HIV neutralizing antibody titers were generated after a single booster immunization. Fully glycosylated HIV trimer protein is a complex antigen, posing significant immunodominance challenges for B cells. Memory B cells (BMem) generated under these long priming conditions had higher levels of SHM, and both BMem cells and antibodies were more likely to recognize non-immunodominant epitopes. Numerous BGC cell lineage phylogenies spanning the >6-month GC period were identified, demonstrating continuous GC activity and selection for at least 191 days with no additional antigen exposure. A long prime, slow delivery (12-day) immunization approach holds promise for difficult vaccine targets, and suggests that patience can have great value for tuning GCs to maximize antibody responses.
2022-09-15 | GSE209904 | GEO
Project description:Productive B cell responses are critical to protect a host from infection. The spleen and lymph nodes are populated by resting follicular B cells, which can enter germinal centers upon antigen encounter. Once in the germinal center, B cells migrate between the dark and light zones, where they undergo somatic hypermutation and selection, respectively. While germinal center B cells have been studied, an intense molecular understanding of these cells/subsets (and the differences between them) is lacking.
2020-04-06 | PXD015524 | Pride
Project description:Germinal centers (GCs) form in secondary lymphoid organs in response to infection and immunization and are the source of affinity-matured B cells. The duration of GC reactions spans a wide range, and long-lasting GCs (LLGCs) are potentially a source of highly mutated B cells. We show that, rather than consisting of continuously evolving B cell clones, LLGCs elicited by influenza virus or SARS-CoV-2 infection in mice are sustained by progressive replacement of founder clones by naïve-derived invader B cells that do not detectably bind viral antigens. Rare founder clones that resist replacement for long periods are enriched in clones with heavily mutated immunoglobulins, including some with very high affinity for antigen, that can be recalled by boosting. Our findings reveal underappreciated aspects of the biology of LLGCs generated by respiratory virus infection and identify clonal replacement as a potential constraint on the development of highly mutated antibodies within these structures.
2022-12-31 | GSE218165 | GEO
Project description:Ig diversification occurs in peripheral lymphoid organs after establishment of central tolerance during B cell development. In germinal centers (GCs), somatic hypermutation of Ig genes occurs in dark zones, followed by selection of mutated clones in light zones (LZs). This generates high-affinity Ig receptors to pathogens but can also produce autoreactive Ig receptors, which are removed by selection mechanisms that are incompletely understood. The ubiquitin ligase Itch prevents the emergence of autoimmune disease and autoantibodies in humans and mice, and patients lacking Itch develop potentially fatal autoimmune diseases; yet, how Itch regulates GC B cells is not well understood. By studying Itch-deficient mice, we have recently shown that Itch directly limits the magnitude of GC responses. Proteomic profiling of GC B cells uncovered that Itch-deficient cells exhibit high mTORC1 and Myc activity, hallmarks of positive selection. Bone marrow chimera and adoptive transfer experiments revealed that B cell Itch restricts noncycling LZ cells. These results support, t our knowledge, a novel role for Itch in skewing selection of GC B cells to restrict LZ accumulation and shape GC-derived humoral immunity. Determining how B cells integrate cues within GCs to navigate through LZs and dark zones will aid in understanding how autoreactive clones emerge from GCs in people with autoimmune disease.
2024-11-12 | PXD040978 | Pride
Project description:Germinal centers (GCs) are the site of immunoglobulin somatic hypermutation and affinity maturation, processes essential to an effective antibody response. The formation of GCs has been studied in detail, but less is known about what leads to their regression and eventual termination, factors that ultimately limit the extent to which antibodies mature within a single reaction. We show that contraction of immunization-induced GCs is immediately preceded by an acute surge in GC-resident Foxp3+ T cells, attributed at least partly to upregulation of the transcription factor Foxp3 by T follicular helper (Tfh) cells. Ectopic expression of Foxp3 in Tfh cells is sufficient to decrease GC size, implicating the natural upregulation of Foxp3 by Tfh cells as a potential regulator of GC lifetimes.
2021-07-15 | GSE173227 | GEO
Project description:Protective immune responses to many pathogens depend on the development of high affinity antibody-producing plasma cells in germinal centers. Transgenic models suggest that there is a stringent affinity-based barrier to plasma cell development. Whether a similar high affinity barrier regulates plasma cell development under physiologic circumstances, and the nature of the plasma cell fate decision has not been defined precisely. Here we use a fate mapping approach to examine the relationship between germinal center (GC) B cells selected to undergo additional rounds of affinity maturation, germinal center pre-plasma cells and plasma cells. The data show that initial plasma cell selection overlaps with germinal center B cell selection, but that the plasma cell compartment accumulates a less diverse and higher affinity collection of antibodies over time. Thus, whereas the GC continues to diversify over time, affinity-based pre-plasma cell selection sieves the germinal center to enable accumulation of a more restricted group of high affinity antibody secreting plasma cells.
2023-11-02 | GSE246382 | GEO
Project description:The Germinal center is a dynamic microenvironment wherein B cells expressing high affinity antibody variants produced by hypermutation are selected for clonal expansion by limiting numbers of T follicular helper cells. Although a great deal is known about the mechanisms that control B cell selection in the germinal center, far less is understood about the clonal behavior of the T follicular helper cells that regulate this process. Here we report on the dynamic behavior of clones of T follicular helper cells during the germinal center reaction. We find that like germinal center B cells, T follicular helper cells undergo antigen dependent selection during the germinal center reaction resulting in differential proliferative expansion and contraction. Increasing the amount of antigen presented in the germinal center leads to increased T follicular cell division. Competition between T follicular helper cell clones is mediated by T cell receptor affinity for peptide-MHC ligand. Higher affinity T cells expanding preferentially in the germinal center show increased expression of genes downstream of the T cell receptor, genes required for metabolic reprogramming, cell division and cytokine production. These dynamic changes lead to dramatic remodeling of the functional T follicular cell repertoire during the germinal center reaction.
2020-03-19 | GSE147182 | GEO