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

ABSTRACT: 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

ORGANISM(S): Mus musculus

SUBMITTER: Wei Shi

PROVIDER: E-GEOD-72831 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Dynamic changes in E protein activity orchestrate germinal center and plasma cell development [ChIP-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. Genome binding of transcription factor E2A

2016-05-13 | E-GEOD-72828 | biostudies-arrayexpress

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

2016-05-13 | GSE72831 | GEO

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

2016-05-13 | GSE72828 | GEO

Blimp1 controls plasma cell physiology and function

Project description:Antibody-secreting plasma cells are the terminal stage of the B-cell lineage. Plasma cell differentiation requires a major resetting of gene expression to silence the B cell transcriptional program, whilst establishing secretory function and long-term survival. The transcription factors Blimp1 and Irf4 are essential for the initial differentiation of activated B cells to antibody-secreting cells, however their function in mature plasma cells remains elusive. We have found that while Irf4 was essential for plasma cell survival, Blimp1 was dispensable. Blimp1-deficient cells retained the unique plasma cell transcriptional signature, but lost the ability to secrete antibody or to maintain the characteristic size and ultrastructure of plasma cells. Blimp1 was required for full expression of many components of the unfolded protein response (UPR), including Xbp1 and Atf6, as well as for the appropriate processing of Igh mRNA. The overlap of Blimp1 and Xbp1 function was restricted to the UPR genes, with Blimp1 uniquely regulating activity of the mTOR pathway, plasma cell size and morphology. These studies establish Blimp1 as a major regulator of the UPR pathway that is also required for the unique metabolic requirements of plasma cells enabling the secretion of protective antibody. RNA-seq was performed on wild type, Blimp1-/- and Xbp1-/- mouse plasma cells. Between two to four biological replicates were generated and sequenced for each sample.

2016-01-18 | E-GEOD-70981 | biostudies-arrayexpress

Essential role of the transcription factors E2A and E2-2 in germinal center B cell and plasma cell development

Project description:E2A is an essential regulator of early B-cell development. Here we demonstrated that E2A together with E2-2 controlled germinal-center B-cell and plasma cell development. As shown by identification of regulated E2A,E2-2 targets in activated B-cells, these E-proteins directly activated genes with important functions in germinal-center B-cells and plasma cells by inducing or maintaining DNase I hypersensitive sites. Through controlling multiple enhancers in the Igh 3â regulatory region and Aicda locus, E-proteins regulated class switching by inducing both Igh germline transcription and AID expression. By regulating 3â Igk enhancers and a distal element at the Prdm1 (Blimp1) locus, E-proteins contributed to Igk, Igh and Prdm1 activation in plasmablasts. These data identified E2A and E2-2 as central regulators of B-cell immunity. 56 samples in total: A) 38 RNA-Seq samples in 5 cell types: Follicular B cells (FO B cell, 2 genotypes, 2 replicates each) Activated B cells (Act B cell, 2 genoytpes, 6 stimulations, 2 replicates each) Pre-Plasmablasts (Pre-PB, 1 genotype, 2 stimulations, 2 replicates each) Plasmablasts (PB, 1 genotype, 2 stimulations, 2 replicates each) Germline Center B cells (GC B cell, 1 genotype, 2 replicates); B) 13 ChIP-Seq samples in 5 cell types: FO B cell (E2A, 2 crosslinking types, 1 replicate each) Act B cell (E2A, 2 crosslinking types, 2 stimulations, 1 replicate each; H3K27ac, 1 crosslinking type, 1 stimulation, 2 genotypes, 1 replicate each) Pre-PB (E2A, 2 crosslinking types, 1 stimulation, 1 replicate each) PB (E2A, 2 crosslinking types, 1 stimulation, 1 replicate each) Mature B cell (input); C) 5 ATAC Seq samples in 2 cell types: Act B cell (2 stimulations, 2 genotypes, 1 replicate each), Pre-PB (1 stimulation, 1 genotype, 1 replicate).

2016-06-01 | E-GEOD-77744 | biostudies-arrayexpress

CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles

Project description:In response to infection, antigen-specific CD8+ T cells are primed in the T cell zone of secondary lymphoid organs and differentiate into cytotoxic effector T (TC) cells. Concurrently, CD4+ T cells differentiate into follicular helper T (TFH) cells that localize to B cell follicles and promote protective antibody responses. During unresolved infections, however, some viruses including human immunodeficiency virus (HIV) or Epsteinâ??Barr virus (EBV) escape immune control and persist in TFH cells and B cells, respectively. Exclusion of Tc cells from B cell follicles is thought to be a major mechanism of immune evasion. New strategies are therefore needed to eradicate infected cells in follicles for a permanent cure. Using mouse infection models and human samples, we here identify a specialized group of TC cells expressing the chemokine receptor CXCR5 that can selectively enter B cell follicles and eradicate infected TFH and B cells. We demonstrate that differentiation of these cells, which we term follicular cytotoxic T (TFC) cells, requires the transcription factors Bcl6, E2A and Tcf1, whereas the transcriptional regulators Blimp1, Id3 and Id2 inhibit their development. We demonstrate that Blimp1 and E2A directly regulate Cxcr5 expression, and together with Bcl6 and Tcf1 form a transcriptional circuit that guides the TFC differentiation. The identification of a follicular subset of TC cells has far reaching implications for developing better strategies for the control of infections that target B cells and TFH cells and for the eradication of B cell derived malignancies. There is no associated input. The E2A Bio-ChIP-seq was performed with total thymocytes from Tcf3Bio/Bio Rosa26BirA/BirA mice

2016-08-01 | E-GEOD-84974 | biostudies-arrayexpress

The DNA-binding inhibitor Id3 regulates IL-9 production in CD4+ T cells

Project description:The molecular mechanisms by which signaling via transforming growth factor-β (TGF-β) and interleukin 4 (IL-4) control the differentiation of IL-9-producing CD4+ helper T cells (TH9 cells) remain incompletely understood. We found here that the DNA-binding inhibitor Id3 regulated TH9 cell differentiation, as deletion of Id3 increased IL-9 production from CD4+ T cells. Mechanistically, TGF-β1 and IL-4 downregulated Id3 expression, and this process required the kinase TAK1. A reduction in Id3 expression enhanced binding of the transcription factors E2A and GATA-3 to the Il9 promoter region, which promoted Il9 transcription. Notably, Id3’s control of TH9 differentiation regulated anti-tumor immunity in an experimental melanoma-bearing model in vivo and also in human CD4+ T cells in vitro. Thus, our study reveals a previously unrecognized TAK1–Id3–E2A–GATA-3 pathway that regulates TH9 differentiation.

2015-08-14 | GSE72051 | GEO

Id3 Orchestrates Germinal Center B Cell Development

Project description:Previous studies have demonstrated that E-proteins induce AID expression in activated B cells. Here we have examined the role of Id3 in germinal center (GC) cells. We found that Id3 expression is high in follicular B-lineage cells but declines in GC cells. Immunized mice depleted for Id3 expression displayed a block in germinal center B cell maturation, showed reduced numbers of marginal zone B cells and class switched cells, were associated with decreased antibody titers and lower numbers of plasma cells. In vitro Id3-depleted B cells displayed a defect in class switch recombination. Whereas AID levels were not altered in Id3-depleted activated B cells, the expression of a subset of genes encoding for signaling components of antigen receptor, cytokine receptor and chemokine receptor mediated signaling was significantly impaired. We propose that during the GC reaction Id3 levels decline to activate the expression of genes encoding for signaling components that mediate B cell receptor and or cytokine-mediated signaling to promote the differentiation of GC B cells.

2016-08-18 | GSE84374 | GEO

Opposing roles of E2A and Id3 that orchestrate and enforce the naive T cell fate

Project description:It is established that E2A and its antagonist, Id3, modulate developmental progression at the pre-TCR and TCR checkpoints. Here we show at a global scale how E2A promotes commitment to the T cell lineage and how pre-TCR mediated signalling affects E2A genome-wide occupancy. We find aberrant development of CD4 memory-like and TFH-like cells, T-B cell conjugates and, remarkably, B cell follicles in Id3-/-thymi. We also find that Id3-/-CD4 splenocytes exhibit increased numbers of TFH-like cells. We propose a model in which Id3 modulates the naive versus effector/memory cell fate. Collectively, these data show how E2A acts globally to orchestrate T-lineage development and that Id3 antagonizes E2A activity beyond the pre-TCR checkpoint to enforce the naive T cell fate.

2011-07-31 | GSE30518 | GEO

BLIMP1 controls GC B cell expansion and exit through regulating cell cycle progression and key transcription factors BCL6 and IRF4

Project description:In B cells BLIMP1 is required for plasma cell differentiation. BLIMP1 is also expressed in some dark zone (DZ) germinal center (GC) B cells (GCBCs), yet the role of BLIMP1 in GCBCs is not understood. Here we generated mixed bone marrow (BM) chimeric mice using Prdm1+/+ CD19Cre and Prdm1fl/fl CD19Cre BM, allowing us to examine the cell-intrinsic functions of BLIMP1 in GCBC, independent of antibody or antigen levels. Strikingly, BLIMP1-deficient B cells quickly dominate GCs and persist for a much longer time compared to the wild type cells. BLIMP1 deficiency promotes positive selection of GCBC and enhances cell-cycle progression. In addition, BLIMP1 deficiency enhanced class-switching. Mechanistically, BLIMP1-deficient GCBC fail to downregulate BCL6 and to upregulate IRF4, indicating that BLIMP1 controls the expression of these transcription factors that mediate exit from the GC. These studies revealed unique functions of BLIMP1 in regulating GCBC responses that impact long-lived immune compartments.

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