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Spatiotemporal dynamics of Bach2 orchestrates B cell responses and fate decision II

ABSTRACT: The molecular circuits that direct early T-dependent B cell responses and alternative cell-fate decisions remain poorly understood. Here, we show that either B cell receptor (BCR) or CD40 signals promoted mTORC1-dependent translation of the transcription factor Bach2. Transient up-regulation of Bach2 protein restrained activated B cell expansion and differentiation into plasma cell while promoting the germinal center (GC) and memory B cell fates at the pre-GC stage. However, enforced Bach2 expression facilitated memory B cell generation versus other cell fates. Mechanistically, Bach2 limited access of AP-1 factors and formed a reciprocal repression loop with IRF4. BCR and CD40 signals also down-regulated Bach2 transcript in antigen-activated B cells, and diversified its abundance in various effector populations, predisposing Bach2 protein expression and subsequent cell-fate choices during memory recall and GC reaction. Thus signaling-induced differential dynamics of Bach2 protein and mRNA in activated B cell control their cell-fate outcomes and imprint the fate of their descendant effector cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE180460 | GEO | 2022/06/08

REPOSITORIES: GEO

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Spatiotemporal dynamics of Bach2 orchestrates B cell responses and fate decision

Project description:The molecular circuits that direct early T-dependent B cell responses and alternative cell-fate decisions remain poorly understood. Here, we show that either B cell receptor (BCR) or CD40 signals promoted mTORC1-dependent translation of the transcription factor Bach2. Transient up-regulation of Bach2 protein restrained activated B cell expansion and differentiation into plasma cell while promoting the germinal center (GC) and memory B cell fates at the pre-GC stage. However, enforced Bach2 expression facilitated memory B cell generation versus other cell fates. Mechanistically, Bach2 limited access of AP-1 factors and formed a reciprocal repression loop with IRF4. BCR and CD40 signals also down-regulated Bach2 transcript in antigen-activated B cells, and diversified its abundance in various effector populations, predisposing Bach2 protein expression and subsequent cell-fate choices during memory recall and GC reaction. Thus signaling-induced differential dynamics of Bach2 protein and mRNA in activated B cell control their cell-fate outcomes and imprint the fate of their descendant effector cells.

2021-07-18 | GSE180277 | 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

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

B cell intrinsic TBK1 is essential for germinal center formation during infection and vaccination

Project description:Germinal center (GC) is a site where somatic hypermutation and clonal selection are coupled for antibody affinity maturation against infections. However, how GCs are formed and regulated is incompletely understood. Here, we identified an unexpected role of Tank-binding kinase-1 (TBK1) as a crucial B-cell-intrinsic factor for GC formation. Using immunization and malaria infection models, we show that TBK1-deficient B cells failed to form GC despite normal Tfh differentiation, although some malaria-infected B-cell-specific TBK1-deficient mice could survive by GC-independent mechanisms. Mechanistically, TBK1 phosphorylation elevates in B cells during GC differentiation and regulates the balance of IRF4/BCL6 expression by limiting CD40 and BCR activation through non-canonical NF-κB and AKTT308 signaling. In the absence of TBK1, CD40 and BCR signaling synergistically enhanced IRF4 expression in Pre-GC leading to BCL6 suppression, therefore failed to form GC. As a result, memory B cells generated from TBK1-deficient B cells fail to confer sterile immunity upon re-infection, suggesting that TBK1 determines B cell fate to promote long-lasting humoral immunity.

2021-12-12 | GSE188659 | GEO

Bach2 promotes B cell receptor-induced proliferation of B lymphocytes and represses cyclin-dependent kinase inhibitors

Project description:Bach2 (BTB and CNC homology-2) is a transcriptional repressor which is required for the formation of the germinal center (GC) and reactions including class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes in B cells within the GC. While BCR-induced proliferation is essential for GC reactions, the function of Bach2 in regulating B cell proliferation has not been elucidated. In this study, we demonstrate that Bach2 is required to sustain high levels of B cell proliferation in response to BCR signaling. Following BCR engagement in vitro, B cells from Bach2-deficient (Bach2-/-) mice showed lower incorporation of 5-bromo-2'-deoxyuridine (BrdU) and reduced cell cycle progression compared with wild-type (WT) cells. Bach2-/- B cells also underwent increased apoptosis as evidenced by an elevated frequency of sub-G1 cells and early apoptotic cells. Transcriptome analysis of BCR-engaged B cells from Bach2-/- mice revealed reduced expression of the anti-apoptotic gene Bcl2l1 encoding Bcl-XL, and an elevated expression of cyclin-dependent kinase inhibitor (CKI) family genes including Cdkn1a, Cdkn2a and Cdkn2b. Reconstitution of Bcl-XL expression partially rescued the proliferation defect of Bach2-/- B cells. Chromatin imunoprecipitation (ChIP) experiments showed that Bach2 bound to the CKI family genes, indicating that these genes are direct repression targets of Bach2. These findings identify Bach2 as a requisite factor for sustaining high levels of BCR-induced proliferation, survival and cell cycle progression, and promotes expression of Bcl-XL and repression of CKI genes, respectively. BCR-induced proliferation defects may contribute to impaired GC formation observed in Bach2-/- mice.

2017-09-21 | GSE103982 | GEO

Bach2 regulates B cell survival to maintain germinal centers and promote B cell memory

Project description:The transcription factor Bach2 serves as a crucial regulator of the germinal center (GC) reaction, which is required for production of high-affinity antibodies and establishment of long-lived B cell memory. However, the stage at which Bach2 controls the GC programs and the precise mechanism underlying these processes remain poorly understood. In this study, we show that genetic ablation of Bach2 in GC B cells of mice impairs their survival and maintenance, and memory B cell formation. These defects can be rescued by enforced expression of anti-apoptotic gene Bcl2. As expected, Bach2-deficient GC B cells are defective in antibody affinity maturation, but have normal somatic hyper mutation and class switch recombination of immunoglobulin genes. Mechanistically, Bach2 controls the GC programs by directly repressing pro-apoptotic gene Bim and a set of genes involved in cell stress response and metabolic processes. Thus, our work reveals the precise roles of Bach2 in the GC biology, and demonstrates that Bach2 acts as a crucial survival regulator of GC B cells, providing a key mechanism underlying GC B maintenance and B cell memory formation.

2022-06-05 | GSE205400 | GEO

Super-killer CTLs are generated by single gene deletion of Bach2

Project description:Bach2 codes for a transcriptional regulator exerting major influences on T cell mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8+ T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient CD8+ T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.

2022-09-02 | PXD036457 | Pride

mTORC1 and B cell survival signal regulate formation of memory precursors in the germinal center [2]

Project description:A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells that survive to become long-lived quiescent memory B cells. We found here that a small population of light zone GC cells (CD38intBcl6hi/intEfnb1+) with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 activity led to defects in formation of the CD38intBcl6hi/intEfnb1+ cells; conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone GC population over the recycling-prone one. Furthermore, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR, which in turn, contributed to their survival. Given the positive correlation between the strength of T cell help and mTORC1 activity, our data suggest a model in which weak help from T cells together with provision of an increased survival signal are key for GC B cells to assume a memory B cell fate.

2020-09-13 | GSE147095 | GEO

mTORC1 and B cell survival signal regulate formation of memory precursors in the germinal center [1]

2020-09-13 | GSE146922 | GEO

Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation

Project description:The transcriptional repressors BCL6 and BACH2 are crucial regulators of germinal center (GC) B-cell fate, and are known to interact and repress transcription of PRDM1, a key driver of plasma cell differentiation. How these factors cooperate is not fully understood. Herein we show that while GC formation is only minimally impaired in Bcl6+/- or Bach2+/- mice, double heterozygous Bcl6+/-Bach2+/- mice exhibit profound reduction in GC formation. Splenic B-cells from Bcl6+/- Bach2+/- mice display accelerated plasmacytic differentiation and high expression of key plasma cell genes such as Prdm1, Xbp1 and CD138. ChIP-seq revealed that in B-cells BACH2 is mostly bound to genes together with its heterodimer partner MAFK. The BACH2-MAFK complex binds to sets of genes known to be involved in the GC response, 60% of which are also targets of BCL6. Approximately 30% of BACH2 peaks overlap with BCL6 including cis-regulatory sequences of the PRDM1 gene. BCL6 also modulates BACH2 protein stability and their protein levels are positively correlated in GC B-cells. Therefore, BCL6 and BACH2 cooperate to orchestrate gene expression patterning in GC B cells through both transcriptional and biochemical mechanisms, which collectively determine the proper initiation and timing of terminal differentiation. ChIP-seq using P18 antibodies in OCI-Ly7 cells

2013-11-17 | E-GEOD-47784 | biostudies-arrayexpress

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