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RNA-seq profiles of germinal center B cells from spleens of wild-type and Il21r-deficient mice after immunization with NP-KLH

ABSTRACT: Humoral immune responses require germinal centres (GC) for antibody affinity maturation. Within GC, B-cell proliferation and mutation are segregated from affinity-based positive selection in the dark zone (DZ) and light zone (LZ) substructures, respectively. While IL21 is known to be important in affinity maturation and GC maintenance, here we show it is required for both establishing normal zone representation and preventing the accumulation of cells in G1 cell cycle stage in the GC LZ.

ORGANISM(S): Mus musculus

PROVIDER: GSE184475 | GEO | 2021/09/22

REPOSITORIES: GEO

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The RNA binding protein PTBP1 is necessary for B cell selection in germinal centres

Project description:Antibody affinity maturation occurs in germinal centres (GC) where B cells cycle between the light zone (LZ) and the dark zone. In the LZ GC B cells bearing immunoglobulins with the highest affinity for antigen receive positive selection signals from T helper cells that promotes their rapid proliferation. Here we show that the RNA binding protein PTBP1 is necessary for the progression of GC B cells through late S-phase of the cell cycle and for affinity maturation. PTBP1 is required for the expression of the c-MYC-dependent gene programme induced in GC B cells receiving T cell help and directly regulates the alternative splicing of transcripts increased during positive selection to promote anabolic metabolism and cell proliferation.

2017-12-06 | GSE100969 | GEO

Comparison of NP specific high and low affinity IgG1 Light zone GC B cells

Project description:Despite the importance of memory B cells for protection from recurrent infection, how these cells are selected during germinal center (GC) reactions remains unclear. We show here that light zone (LZ) GC B cells with lower affinity BCRs express a less CD40 signature and relatively high levels of Bach2, being prone to enter the memory B cell pool. We also find that Bach2 contributes to memory B cell generation in a Blimp-1 independent manner and that its higher expression confers on LZ GC cells a more advantage for entering the memory B cell compartment. Thus, our data support an instructive model in which weak T cell help keeps Bach2 expression relatively high, thereby being predisposed to enter the memory pool.

2016-05-09 | GSE73729 | GEO

Comparison of Bach2-tdRFP high expression and low expression NP-specific IgG1 light zone GC B cells

Project description:Despite the importance of memory B cells for protection from recurrent infection, how these cells are selected during germinal center (GC) reactions remains unclear. We show here that light zone (LZ) GC B cells with lower affinity BCRs express a less CD40 signature and relatively high levels of Bach2, being prone to enter the memory B cell pool. We also find that Bach2 contributes to memory B cell generation in a Blimp-1-independent manner and that its higher expression confers on LZ GC cells a more advantage for entering the memory B cell compartment. Thus, our data support an instructive model in which weak T cell help keep Bach2 expression relatively high, thereby being predisposed to enter the memory pool.

2016-05-09 | GSE77319 | GEO

STAT3 signaling in B cells controls germinal center zone organization and recycling [RNA-seq]

Project description:Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we uncovered a B cell intrinsic role for STAT3 in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampened GC output of long-lived plasma cells (LL-PCs) but increased memory B cells (MBCs). Tfh-GC B cell interaction drive STAT3 tyrosine 705 and serine 727 phosphorylation in LZ B cells, facilitating their recycling into the DZ. An inducible system confirmed STAT3 is not involved in initiating or maintaining the GC but sustains GC zonal organization by regulating GC B cell recycling. RNAseq and ChIPseq analysis identified genes regulated by STAT3 that are critical for LZ cell recycling and transiting through the DZ proliferation and differentiation phases of the DZ. Thus, STAT3 signaling in B cells controls GC zone organization and recycling, and GC egress of LL-PCs, but negatively regulates MBC output.

2023-07-06 | GSE212542 | GEO

STAT3 signaling in B cells controls germinal center zone organization and recycling [ChIP-seq]

Project description:Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we uncovered a B cell intrinsic role for STAT3 in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampened GC output of long- lived plasma cells (LL-PCs) but increased memory B cells (MBCs). Tfh-GC B cell interaction drive STAT3 tyrosine 705 and serine 727 phosphorylation in LZ B cells, facilitating their recycling into the DZ. An inducible system confirmed STAT3 is not involved in initiating or maintaining the GC but sustains GC zonal organization by regulating GC B cell recycling. RNAseq and ChIPseq analysis identified genes regulated by STAT3 that are critical for LZ cell recycling and transiting through the DZ proliferation and differentiation phases of the DZ. Thus, STAT3 signaling in B cells controls GC zone organization and recycling, and GC egress of LL- PCs, but negatively regulates MBC output.

2023-07-06 | GSE212541 | GEO

Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells

Project description:Germinal centers (GCs) are the sites of affinity maturation, the process by which antibodies improve their affinity for antigen over time (Cyster and Allen, 2019; De Silva and Klein, 2015; Eisen, 2014; Mesin et al., 2016; Rajewsky, 1996; Shlomchik et al., 2019; Victora and Nussenzweig, 2012). For efficient affinity maturation, GC B cells must cycle between two major transcriptional states, associated with localization of B cells to each of the two microanatomical “zones” of the GC. When in the dark zone (DZ), B cells proliferate vigorously while they mutate their immunoglobulin genes by somatic hypermutation (SHM). After transition to the light zone (LZ), B cells bearing advantageous mutations are selectively driven to clonally expand, based at least in part on their ability to bind and present antigen to GC-resident T follicular helper (Tfh) cells (Victora et al., 2010). Successive cycles of somatic hypermutation and affinity-based selection ultimately enrich for higher-affinity cells in among the GC B cell population, in a process known as cyclic re-entry (MacLennan, 1994; Victora and Nussenzweig, 2012).

2020-12-10 | GSE162182 | GEO

Transcription factor T-bet in B cells controls germinal centre polarization and antibody affinity maturation in response to malaria (RNA-seq)

Project description:Despite the key role that antibodies play in protection against malaria, the cellular processes modulating the acquisition of immunity are not fully understood. Using an infection model of severe malaria, we found that GC B cells strongly upregulate the transcription factor T-bet in response to infection. Expression of T-bet in B cells was required for IgG2c switching but reduced the magnitude of GC B cell responses. RNA-sequencing and flow cytometry analysis revealed that T-bet supports a transcriptional program resulting in a substantial enrichment of the GC dark zone (DZ), thereby significantly influencing DZ/light zone (LZ) polarization. Mice deficient in T-bet in their B cells displayed significantly reduced affinity mutation frequencies in their IghV genes and lower antibody avidity than controls, indicating that T-bet modulates affinity maturation. These results demonstrate that T-bet promotes appropriate GC dynamics, thereby leading to the differentiation of B cells with increased affinity for antigen.

2019-11-11 | GSE120728 | GEO

Transcription factor T-bet in B cells controls germinal centre polarization and antibody affinity maturation in response to malaria (ATAC-seq)

2019-11-11 | GSE120727 | GEO

Germinal Center Dark Zone harbors ATR-dependent determinants of T-cell exclusion that are also identified in aggressive lymphoma – Visium_FFPE_Spatial_Trasciptomics_project

Project description:The germinal center (GC) dark zone (DZ) and light zone (LZ) regions spatially separate expansion and diversification from selection of antigen-specific B-cells to ensure antibody affinity maturation and B cell memory. How GC polarity is established is poorly understood. This study provides novel insights into signals controlling asymmetric T-cell distribution between DZ and LZ regions. We identify spatially-resolved DNA damage response and chromatin compaction molecular features precluding DZ T-cell infiltration. The DZ spatial transcriptional signature linked to T-cell immune evasion clustered aggressive Diffuse Large B-cell Lymphomas (DLBCL) for differential T cell infiltration. We reveal the dependence of the DZ transcriptional core signature on the ATR kinase and dissect its role in restraining inflammatory responses contributing to estabslish an immune-repulsive imprint in DLBCL. These insights may guide ATR-focused treatment strategies bolstering immunotherapy in tumors marked by DZ transcriptional and chromatin-associated features.

2024-04-17 | GSE260998 | GEO

T cell help controls the speed of the cell cycle in germinal center B cells.

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.

2015-08-12 | GSE71295 | GEO

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