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Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (RNA-Seq)

ABSTRACT: Upon antigen recognition B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GC). We uncover a double negative feedback loop between interferon regulatory factors IRF4 and IRF8, which regulates the initial bifurcation of activated B cells as well as the GC response. IRF8 dampens BCR signaling, facilitates antigen specific interaction with helper T cells, and promotes selection of high affinity clones while antagonizing IRF4 driven plasmablast differentiation. Genomic analysis reveals concentration dependent action of IRF4 and IRF8 in regulating distinctive gene expression programs. Stochastic modeling suggests that the double negative feedback is sufficient to initiate bifurcating B cell developmental trajectories.

ORGANISM(S): Mus musculus

PROVIDER: GSE70711 | GEO | 2015/08/25

SECONDARY ACCESSION(S): PRJNA289409

REPOSITORIES: GEO

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Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (ChIP-Seq)

2015-08-25 | GSE70710 | GEO

Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (RNA-Seq)

Project description:Upon antigen recognition B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GC). We uncover a double negative feedback loop between interferon regulatory factors IRF4 and IRF8, which regulates the initial bifurcation of activated B cells as well as the GC response. IRF8 dampens BCR signaling, facilitates antigen specific interaction with helper T cells, and promotes selection of high affinity clones while antagonizing IRF4 driven plasmablast differentiation. Genomic analysis reveals concentration dependent action of IRF4 and IRF8 in regulating distinctive gene expression programs. Stochastic modeling suggests that the double negative feedback is sufficient to initiate bifurcating B cell developmental trajectories. Naïve B cells were isolated from Irf8+/+ (wild type, WT) mice spleen and activated in vitro with 10μg/ml LPS (Sigma). CD138hi IgMhi (IRF4hi*) cells and CD138lo IgMlo (IRF8hi*) cells were sorted by flow cytometry at 72 hours. Total RNA was prepared by using Rneasy Mini kit (Qiagen) and sequenced with Illumina HiSeq2500. Alignment was performed with Taphat2, and transcript abundance quantification using Cuffdiff function from Cufflinks. GC B cells were sorted from CD19cre/+ Irf8+/+ (Ctrl) or CD19cre/+ Irf8flox/flox (Irf8 cKO) mice on dpi 13 post NP-KLH immunization. Total RNA was prepared by using Rneasy Mini kit (Qiagen) and amplified with with Ovation RNA-Seq System v2 (NuGEN). The data were analyzed by Wardrobe. More details are provided in the manuscript.

2015-08-25 | E-GEOD-70711 | biostudies-arrayexpress

Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (ChIP-Seq)

Project description:Upon antigen recognition B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GC). We uncover a double negative feedback loop between interferon regulatory factors IRF4 and IRF8, which regulates the initial bifurcation of activated B cells as well as the GC response. IRF8 dampens BCR signaling, facilitates antigen specific interaction with helper T cells, and promotes selection of high affinity clones while antagonizing IRF4 driven plasmablast differentiation. Genomic analysis reveals concentration dependent action of IRF4 and IRF8 in regulating distinctive gene expression programs. Stochastic modeling suggests that the double negative feedback is sufficient to initiate bifurcating B cell developmental trajectories. Naïve B cells were isolated from wild type (WT) mice spleen and activated in vitro with 10μg/ml LPS (Sigma). ChIP was performed by using anti-IRF4, -IRF8 antibodies (Santa Cruz Biotech). For massively parallel sequencing, 10-20 μg of chromatin fragments from indicated samples were immunoprecipitated by using anti-IRF-4 and anti-IRF8 antibodies, and DNA libraries were prepared with Illumina Kit. DNA was sequenced by using the Illumina HiSeq2500. Reads were aligned to the mouse genome (mm9) by using Taphat2 and peak calling were performed by homer 2. GC B cells were sorted from WT mice on dpi 13 post NP-KLH immunization. Cells were flash frozen immediately and process by Active Motif for IRF8 ChIP-Seq. Reads were aligned to mm9 by using BAM and peak calling were performed by using MACS. More details are provided in the manuscript.

2015-08-25 | E-GEOD-70710 | biostudies-arrayexpress

Project description:Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8

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Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses

Project description:Subset-specific and progenitor gene expression analysis of Klf4+/+ and Klf4-/- DCs. The two major lineages of classical dendritic cells (cDCs) express and require either IRF8 or IRF4 transcription factors for their development and function. IRF8-dependent cDCs promote anti-viral and T-helper 1 (Th1) cell responses, whereas IRF4-expressing cDCs have been implicated in controlling both Th2 and Th17 cell responses. Here, we have provided evidence that Kruppel-like factor 4 (Klf4) is required in IRF4-expressing cDCs to promote Th2 but not Th17 cell responses in vivo. Conditional Klf4 deletion within cDCs impaired Th2 cell responses during Schistosoma mansoni infection, Schistosoma egg antigen (SEA) immunization, and house dust mite challenge (HDM), without affecting cytotoxic T lymphocyte (CTL), Th1 and Th17 cell responses to herpes simplex virus, Toxoplasma gondii and Citrobacter rodentium infections. Further, Klf4 deletion reduced IRF4 expression in pre-cDCs and resulted in selective loss of IRF4-expressing cDCs subsets in several tissues. These results indicate that Klf4 guides a transcriptional program promoting IRF4-expressing cDCs heterogeneity. Bone marrow progenitors and skin draining LN subsets were harvested from 4 Klf4fl/fl cre negative or Vav1-icre mice and were sorted to >95% purity on the FACS Aria 3.

2015-05-19 | E-GEOD-68590 | biostudies-arrayexpress

Development of plasma cell-prone germinal center B cells

Project description:Higher- or lower-affinity GC B cells are directed to plasma cell or recycling GC cell fates; however, how commitment to the plasma cell fate takes place is unclear. By using the level of Bcl6 as a marker, we found that a population of light zone (LZ) GC cells, Bcl6loCD69hi with IRF4 and higher-affinity BCRs or Bcl6hiCD69hi with lower- affinity BCRs, favored the plasma cell or recycling GC cell fate, respectively. Mechanistically, CD40 acted as a dose-dependent regulator for Bcl6loCD69hi cell formation. Furthermore, we found that ICAM1 and SLAM levels on Bcl6loCD69hi cells were higher than on Bcl6hiCD69hi cells, thereby affording more stable TFH-GC B cell contacts, while attenuating this contact down-regulated IRF4. These data support the model that commitment to the plasma cell begins in the GC, and suggest that stability and possibly duration of TFH-GC B cell contacts are key for formation of plasma cell-prone precursor GC cells.

2018-03-29 | GSE109732 | GEO

Transcription factors IRF8 and PU.1 are required for follicular B cell development and BCL6-driven germinal center responses

Project description:The IRF and Ets families of transcription factors regulate the expression of a range of genes involved in immune cell development and function. However, the understanding of molecular mechanisms of each family member has been limited due to their redundancy and broad effects on multiple lineages of cells. Here, we report that double deletion of floxed Irf8 and Spi1 (encoding PU.1) by Mb1-Cre (designated DKO mice) in the B cell lineage resulted in severe defects in the development of follicular and germinal center (GC) B cells. Class switch recombination and antibody affinity maturation were also compromised in DKO mice. RNA-seq and ChIP-seq analyses revealed distinct IRF8 and PU.1 target genes in follicular and activated B cells. DKO B cells had diminished expression of target genes vital for maintaining follicular B cell identity and GC development. Moreover, our findings reveal that expression of BCL6, which is critical for development of germinal center B cells, is dependent on IRF8 and PU.1 in vivo, providing a mechanism for the critical role for IRF8 and PU.1 in the development of GC B cells.

2019-03-30 | GSE128166 | GEO

Mus musculus

Project description:Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (RNA-Seq)

| PRJNA289409 | ENA

Mus musculus

Project description:Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (ChIP-Seq)

| PRJNA289410 | ENA

Dynamic changes in E protein activity orchestrate germinal center and plasma cell development [RNA-Seq]

Project description:Humoral immunity requires the generation of high-affinity antibodies, which involves the generation of germinal centres (GC) promoting class switch and affinity maturation of antigen-specific B cells, and the differentiation of long-lived plasma cells. This multi-layered process is tightly controlled by the activity of a transcriptional network including Bcl6, essential for the development of GC, and Blimp1, required for the differentiation of plasma cells. Here, we reveal an additional layer of complexity by demonstrating that dynamic changes in E-protein activity mediated by Id3 govern both GC and plasma cell differentiation. We show that down-regulation of Id3 expression in B cells in essential for releasing E2A and E2-2, the combined activity of which is required for both GC B cell and plasma cell differentiation. We demonstrate that this pathway controls the expression of multiple key factors required for antigen-induced B cell differentiation, including Blimp1, Xbp1, Mef2b and CXCR4 and is therefore critical for establishing the transcriptional network that controls GC B cell and plasma cell differentiation. Transcriptional profiling of wild type, Id3 knockout and E2A/E22 double knockout B cells using RNA sequencing

2016-05-13 | E-GEOD-72831 | biostudies-arrayexpress

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