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| Status |
Public on Dec 12, 2021 |
| Title |
B cell intrinsic TBK1 is essential for germinal center formation during infection and vaccination |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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.
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| Overall design |
mRNA profiles of wild-type Pre-GC B cells and Tbk1-deficient Pre-GC B cells were generated by RNA sequencing using Illumina Novaseq 6000
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| Contributor(s) |
Lee MS, Matsuo-Dapaah J, Coban C |
| Citation(s) |
34910106 |
| |
| Submission date |
Nov 12, 2021 |
| Last update date |
Mar 13, 2022 |
| Contact name |
Michelle Sue Jann Lee |
| E-mail(s) |
msj-lee@ims.u-tokyo.ac.jp
|
| Organization name |
The University of Tokyo
|
| Department |
Institute of Medical Science
|
| Street address |
Minato-ku, Shirokanedai 4-6-1, Building 1, 3F, Room 333
|
| City |
Tokyo |
| State/province |
Tokyo |
| ZIP/Postal code |
1088639 |
| Country |
Japan |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA779866 |
| SRA |
SRP345726 |
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