B cell intrinsic TBK1 is essential for germinal center formation during infection and vaccination
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA779866 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16925472.fastq.gz | Fastqsanger.gz | |||
| SRR16925473.fastq.gz | Fastqsanger.gz | |||
| SRR16925474.fastq.gz | Fastqsanger.gz | |||
| SRR16925475.fastq.gz | Fastqsanger.gz | |||
| SRR16925476.fastq.gz | Fastqsanger.gz |
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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
Project description:The 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 cell 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 noncanonical 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, and therefore failed to form GCs. As a result, memory B cells generated from TBK1-deficient B cells fail to confer sterile immunity upon reinfection, suggesting that TBK1 determines B cell fate to promote long-lasting humoral immunity.
| S-EPMC8679780 | biostudies-literature
Project description:By investigating the germinal center (GC) formation in STAT6ko/WT bone marrow-mixed chimera we found that GC formation in type 2 immune responses is dependent on B cell intrinsic expression of IL-4/IL-13-induced genes. We therefore used microarrays to find Stat6 dependent genes that are important for germinal center formation and/or organization after infection with the nematode Nippostrongylus brasiliensis (N. brasiliensis). Bone marrow of STAT6ko (CD45.2+) and WT (CD45.1+) were mixed and injected in lethaly irradiated WT (CD45.1+) mice. After 8 weeks, 5 Bone marrow-mixed chimera were infected with N. brasiliensis and draining lymph nodes were collected at day 14 after the infection and pooled. RNA was isolated from sort-purified CD45.1+ or CD45.2+ GC B cells (B220+CD38loGL-7hi).
2014-05-26 | E-GEOD-47679 | biostudies-arrayexpress
Project description:By investigating the germinal center (GC) formation in STAT6ko/WT bone marrow-mixed chimera we found that GC formation in type 2 immune responses is dependent on B cell intrinsic expression of IL-4/IL-13-induced genes. We therefore used microarrays to find Stat6 dependent genes that are important for germinal center formation and/or organization after infection with the nematode Nippostrongylus brasiliensis (N. brasiliensis).
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Project description:Productive B cell responses are critical to protect a host from infection. The spleen and lymph nodes are populated by resting follicular B cells, which can enter germinal centers upon antigen encounter. Once in the germinal center, B cells migrate between the dark and light zones, where they undergo somatic hypermutation and selection, respectively. While germinal center B cells have been studied, an intense molecular understanding of these cells/subsets (and the differences between them) is lacking.
2020-04-06 | PXD015524 | Pride
Project description:Lupus patients respond less efficiently to vaccinations and are more susceptible to infections. Previously, we have shown, in lupus models, that excessive CD11c+ age-associated B cells (ABCs) not only contribute to autoantibody production but also compromise antigen-specific germinal center (GC) B cell selection and affinity maturation by promoting aberrant T cell activation. Yet, how CD11c+ ABC differentiation is regulated is not fully understood. Here we show that B cell-intrinsic IFN-γ is required for excessive CD11c+ ABC differentiation in lupus mice. B cell-intrinsic IFN-γ is mainly produced by CD11c+ ABCs. IFN-γ-deficiency leads to decreased expression of ABC characteristic genes, including Zeb2, an ABC-specific transcription factor recently described. We further show that ablating IFN-γ can normalize T cell overactivation and rescue antigen-specific GC responses in lupus mice. Our study offers insight into the crucial role of B cell-intrinsic IFN-γ in promoting CD11c+ ABC differentiation and compromising affinity-based germinal center selection and affinity maturation in lupus, providing a potential target for lupus treatment.
2024-07-13 | GSE271698 | GEO
Project description:It is well-established that the five transcription factors of the NFκB family form homo/hetero dimers amongst themselves to regulate gene expression by binding DNA. Our study challenges this paradigm by showing that p52 activates transcription without directly binding DNA but as part of a hetero-tetrameric partnership with ETS1, a transcription factor outside the NFκB family. By generating a knock-in mouse model (p52ki/ki) with three mutated residues on p52 required for its interactions with ETS1 but not with RelB, we demonstrate that the p52:ETS1 complex is the hitherto undiscovered regulator of transcription factors, OCT1 and OBF1, known to be critical for the germinal centre (GC) program. Consequently B cell-intrinsic expression of p52:ETS1 complex is indispensable for splenic GC B cell formation and T cell-dependent antibody responses. Functionally, loss of p52:ETS1 interaction led to diminished antigen-specific IgE thereby protecting mice from allergic responses. Collectively, our expand our current knowledge of NFkB signalling and provide new therapeutic targets for the treatment of allergic diseases.
2025-07-26 | GSE300336 | GEO
Project description:It is well-established that the five transcription factors of the NFκB family form homo/hetero dimers amongst themselves to regulate gene expression by binding DNA. Our study challenges this paradigm by showing that p52 activates transcription without directly binding DNA but as part of a hetero-tetrameric partnership with ETS1, a transcription factor outside the NFκB family. By generating a knock-in mouse model (p52ki/ki) with three mutated residues on p52 required for its interactions with ETS1 but not with RelB, we demonstrate that the p52:ETS1 complex is the hitherto undiscovered regulator of transcription factors, OCT1 and OBF1, known to be critical for the germinal centre (GC) program. Consequently B cell-intrinsic expression of p52:ETS1 complex is indispensable for splenic GC B cell formation and T cell-dependent antibody responses. Functionally, loss of p52:ETS1 interaction led to diminished antigen-specific IgE thereby protecting mice from allergic responses. Collectively, our expand our current knowledge of NFkB signalling and provide new therapeutic targets for the treatment of allergic diseases.
2025-07-26 | GSE300335 | GEO
Project description:It is well-established that the five transcription factors of the NFκB family form homo/hetero dimers amongst themselves to regulate gene expression by binding DNA. Our study challenges this paradigm by showing that p52 activates transcription without directly binding DNA but as part of a hetero-tetrameric partnership with ETS1, a transcription factor outside the NFκB family. By generating a knock-in mouse model (p52ki/ki) with three mutated residues on p52 required for its interactions with ETS1 but not with RelB, we demonstrate that the p52:ETS1 complex is the hitherto undiscovered regulator of transcription factors, OCT1 and OBF1, known to be critical for the germinal centre (GC) program. Consequently B cell-intrinsic expression of p52:ETS1 complex is indispensable for splenic GC B cell formation and T cell-dependent antibody responses. Functionally, loss of p52:ETS1 interaction led to diminished antigen-specific IgE thereby protecting mice from allergic responses. Collectively, our expand our current knowledge of NFkB signalling and provide new therapeutic targets for the treatment of allergic diseases.
2025-07-26 | GSE300334 | GEO
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