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Project description:Germinal Center (GC) B cellsconstitutekey effectorsofthehumoral immune responseandundergoiterativerounds ofproliferation, somatic hypermutationof their immunoglobulin genesand eventuallycompete for T follicular helper (TFH) cellshelpin order togenerate cells with high affinity B cell receptor (BCR).While selected cells passing the critical TFHfitness checkpointcan differentiate toplasma cells,memory B cellsor go through additional rounds of proliferation and mutagenesis, the mechanisms enabling fully differentiated GCs to re-acquire plasticity–usually lost upon cell fate specification–arestill largely unknown.Herein,we report that matureGCsundergo a physiologicaltransientstate characterized byanincreased functional plasticity andinduced pluripotent stem cell (iPSC)reprogramming capacity.This transition state isreminiscent of anaplasisdue to theconcomitantpartial activation of embryonic stem cellandattenuation of the B cell programs.We furthermore demonstrate thatGC anaplasisis dependent on TFHcells sincein vivointerference of TFH:GC B cells communication or lymphoma driver mutationsaffectingGCsresponse to TFHcell help were shown to modulate their reprogramming efficiency accordingly. Importantly, GC stem-like gene signatures, as revealed by single-cell Multiome analysis of thistransient anaplastic state, were often enriched inDiffuse Large B cell lymphoma (DLBCL)patients and associate with poor outcomes, suggesting that this rare preexisting plastic state might be hijacked and further enhancefitnessduring lymphomagenesis.
2025-10-29 | GSE249427 | GEO
Project description:During cellular differentiation, phenotypic plasticity is gradually lost due to the strengthening of epigenetic barriers, although it may be re-acquired upon disease or injury. Here, we report an unprecedented physiological gain of epigenetic plasticity among mature B cells during the humoral immune response. Acquisition of plasticity was strictly dependent on T follicular helper (TFH) cells and restricted to germinal center (GC) but not activated B cells, indicating both non- and cell-autonomous contributions to this phenotype. Importantly, GC plasticity was not dependent on proliferation and could not be solely explained by the activation of MYC programs. Instead, GC plasticity was associated with the reciprocal weakening of B cell identity and the de- repression of progenitor and stem cell-like programs induced by NFκB and other signals, downstream of TFH signaling. Therefore, physiological acquisition of GC B cell plasticity is tightly controlled by the affinity maturation positive selection checkpoint. Notably, Histone 1 loss of function, which results in aberrant stem cell gene reactivation through chromatin decompaction, allowed GC B cells to bypass this gatekeeping mechanism. Finally, patients with Diffuse LargeB Cell Lymphoma (DLBCL) that enriched for GC plasticity signatures had significantly worse outcomes, implicating a role for this mechanism in immune regulation and fitness and potential relevance to lymphomagenesis.
2025-10-29 | GSE298425 | GEO
Project description:During cellular differentiation, phenotypic plasticity is gradually lost due to the strengthening of epigenetic barriers, although it may be re-acquired upon disease or injury. Here, we report an unprecedented physiological gain of epigenetic plasticity among mature B cells during the humoral immune response. Acquisition of plasticity was strictly dependent on T follicular helper (TFH) cells and restricted to germinal center (GC) but not activated B cells, indicating both non- and cell-autonomous contributions to this phenotype. Importantly, GC plasticity was not dependent on proliferation and could not be solely explained by the activation of MYC programs. Instead, GC plasticity was associated with the reciprocal weakening of B cell identity and the de- repression of progenitor and stem cell-like programs induced by NFκB and other signals, downstream of TFH signaling. Therefore, physiological acquisition of GC B cell plasticity is tightly controlled by the affinity maturation positive selection checkpoint. Notably, Histone 1 loss of function, which results in aberrant stem cell gene reactivation through chromatin decompaction, allowed GC B cells to bypass this gatekeeping mechanism. Finally, patients with Diffuse LargeB Cell Lymphoma (DLBCL) that enriched for GC plasticity signatures had significantly worse outcomes, implicating a role for this mechanism in immune regulation and fitness and potential relevance to lymphomagenesis.
2025-10-29 | GSE298424 | GEO
Project description:The germinal center (GC) is a microanatomical compartment wherein high-affinity antibody-producing B cells are selectively expanded. B cells proliferate and mutate their antibody genes in the dark zone (DZ) of the GC and are then selected by T cells in the light zone (LZ) on the basis of affinity. Here, we show that T cell help regulates the speed of cell cycle phase transitions and DNA replication of GC B cells. Genome sequencing and single-molecule analyses revealed that T cell help shortens S phase by regulating replication fork progression, while preserving the relative order of replication origin activation. Thus, high-affinity GC B cells are selected by a mechanism that involves prolonged dwell time in the DZ where selected cells undergo accelerated cell cycles.
| S-EPMC4809261 | biostudies-literature
Project description:This data is related to the research article entitled "Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy" (Harper et al., 2016) [2]. The data presented here focuses on the humoral autoimmune response triggered by transferred allogeneic CD4 T cells and includes details on: (a) the recipient splenic germinal center (GC) response; (b) augmentation of humoral autoimmunity and accelerated heart allograft rejection following transplantation from donors primed against recipient; (c) flow cytometric analysis of donor and recipient CD4 T cells for signature markers of T follicular helper cell differentiation; (d) in vitro donor endothelial cell migration in response to column purified autoantibody from recipient sera; (e) analysis of development of humoral responses in recipients following adoptive transfer of donor CD4 T cells and; (f) the development of humoral autoimmunity in mixed haematopoietic chimeric mice.
| S-EPMC6327748 | biostudies-literature
Project description:Germinal center (GC) B cells are among the fastest replicating cells in our body, dividing every 4-8 h. DNA replication errors are intrinsically toxic to cells. How GC B cells exert control over the DNA damage response while introducing mutations in their antibody genes is poorly understood. Here, we show that the DNA damage response regulator Checkpoint kinase 1 (CHK1) is essential for GC B cell survival. Remarkably, effective antibody-mediated immunity relies on optimal CHK1 dosage. Chemical CHK1 inhibition or loss of one Chk1 allele impairs the survival of class-switched cells and curbs the amplitude of antibody production. Mechanistically, active B cell receptor signaling wires the outcome of CHK1-inhibition towards BIM-dependent apoptosis, whereas T cell help favors temporary cell cycle arrest. Our results predict that therapeutic CHK1 inhibition in cancer patients may prove potent in killing B cell lymphoma and leukemia cells addicted to B cell receptor signaling, but will most likely dampen humoral immunity.
| S-EPMC7224292 | biostudies-literature
Project description:"Extended priming" immunization regimens that prolong exposure of the immune system to vaccines during the primary immune response have shown promise in enhancing humoral immune responses to a variety of subunit vaccines in preclinical models. We previously showed that escalating-dosing immunization (EDI), where a vaccine is dosed every other day in an increasing pattern over 2 weeks dramatically amplifies humoral immune responses. But such a dosing regimen is impractical for prophylactic vaccines. We hypothesized that simpler dosing regimens might replicate key elements of the immune response triggered by EDI. Here we explored "reduced ED" immunization regimens, assessing the impact of varying the number of injections, dose levels, and dosing intervals during EDI. Using a stabilized HIV Env trimer as a model antigen combined with a potent saponin adjuvant, we found that a two-shot extended-prime regimen consisting of immunization with 20% of a given vaccine dose followed by a second shot with the remaining 80% of the dose 7 days later resulted in increased total GC B cells, 5-10-fold increased frequencies of antigen-specific GC B cells, and 10-fold increases in serum antibody titers compared to single bolus immunization. Computational modeling of the GC response suggested that this enhanced response is mediated by antigen delivered in the second dose being captured more efficiently as immune complexes in follicles, predictions we verified experimentally. Our computational and experimental results also highlight how properly designed reduced ED protocols enhance activation and antigen loading of dendritic cells and activation of T helper cells to amplify humoral responses. These results suggest that a two-shot priming approach can be used to substantially enhance responses to subunit vaccines.
| S-EPMC10690148 | biostudies-literature
Project description:Hypoxia develops in germinal centers (GCs) induced by model antigens; however, it is unknown whether tumor-reactive GCs are also hypoxic. We identified GC hypoxia in lymph nodes (LNs) draining murine mammary tumors and lethally irradiated tumor cells, and found that hypoxia is associated with the levels of antibody-secreting B cells. Hypoxic culture conditions impaired the proliferation of activated B cells, and inhibited class-switching to IgG1 and IgA immunoglobulin isotypes in vitro. To assess the role of the hypoxic response in tumor-reactive GCs in vivo, we deleted von Hippel-Lindau factor (VHL) in class-switched B cells and found decreased GC B cells in tumor-draining LNs, reduced class-switched and tumor-specific antibodies in the circulation, and modified phenotypes of tumor-infiltrating T cells and macrophages. We also detected the hypoxia marker carbonic anhydrase IX in the GCs of LNs from breast cancer patients, providing evidence that GC hypoxia develops in humans. We conclude that GC hypoxia develops in TDLNs, and that the hypoxic response negatively regulates tumor-induced humoral immune responses in preclinical models.
| S-EPMC8344742 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-12-04 | GSE139198 | GEO
Project description:Age-related reductions in vaccine-induced B cells in aging indicate that germinal centers (GCs), the anatomical site where the development of humoral responses takes place, may lose efficacy with age. We have investigated the baseline follicular and GC composition in nonhuman primates (NHPs) with respect to their age. There was a marked reduction in follicular area in old animals. We found significantly lower normalized numbers of follicular PD1hi CD4 T (Tfh) and proliferating (Ki67hi ) GC B cells with aging, a profile associated with significantly higher numbers of potential follicular suppressor FoxP3hi Lag3hi CD4 T cells. Furthermore, a positive correlation was found between Tfh and follicular CD8 T cells (fCD8) only in young animals. Despite the increased levels of circulating preinflammatory factors in aging, young animals had higher numbers of monocytes and granulocytes in the follicles, a profile negatively associated with numbers of Tfh cells. Multiple regression analysis showed an altered association between GC B cells and other GC immune cell populations in old animals suggesting a differential mechanistic regulation of GC activity in aging. Our data demonstrate defective baseline GC composition in old NHPs and provide an immunological base for further understanding the adaptive humoral responses with respect to aging.
| S-EPMC6996951 | biostudies-literature