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Lee MSJ, Inoue T, Ise W, et al. B cell-intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice. J Exp Med. 2021;219(2)doi: 10.1084/jem.20211336.
Lee, M. S. J., Inoue, T., Ise, W., Matsuo-Dapaah, J., Wing, J. B., Temizoz, B., Kobiyama, K., Hayashi, T., Patil, A., Sakaguchi, S., Simon, A. K., Bezbradica, J. S., Nagatoishi, S., Tsumoto, K., Inoue, J. I., Akira, S., Kurosaki, T., Ishii, K. J., & Coban, C. (2022). B cell-intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice. The Journal of experimental medicine, 219(2), . https://doi.org/10.1084/jem.20211336
Lee, Michelle S J, et al. "B cell-intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice." The Journal of experimental medicine vol. 219,2 (2022). doi: https://doi.org/10.1084/jem.20211336
Lee MSJ, Inoue T, Ise W, Matsuo-Dapaah J, Wing JB, Temizoz B, Kobiyama K, Hayashi T, Patil A, Sakaguchi S, Simon AK, Bezbradica JS, Nagatoishi S, Tsumoto K, Inoue JI, Akira S, Kurosaki T, Ishii KJ, Coban C. B cell-intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice. J Exp Med. 2022 Feb 07;219(2). doi: 10.1084/jem.20211336. Epub 2021 Dec 15. PMID: 34910106; PMCID: PMC8679780.
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J Exp Med. 2022 Feb 07;219(2). doi: 10.1084/jem.20211336. Epub 2021 Dec 15.

B cell-intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice.

The Journal of experimental medicine

Michelle S J Lee, Takeshi Inoue, Wataru Ise, Julia Matsuo-Dapaah, James B Wing, Burcu Temizoz, Kouji Kobiyama, Tomoya Hayashi, Ashwini Patil, Shimon Sakaguchi, A Katharina Simon, Jelena S Bezbradica, Satoru Nagatoishi, Kouhei Tsumoto, Jun-Ichiro Inoue, Shizuo Akira, Tomohiro Kurosaki, Ken J Ishii, Cevayir Coban

Affiliations

  1. Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  2. International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  3. Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
  4. Laboratory of Human Immunology (Single Cell Immunology), Immunology Frontier Research Center, Osaka University, Osaka, Japan.
  5. Human Single Cell Immunology Team, Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan.
  6. Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  7. Combinatics Inc., Tokyo, Japan.
  8. Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
  9. The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
  10. Research Platform Office, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  11. Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
  12. Immunology Frontier Research Center, Osaka University, Osaka, Japan.

PMID: 34910106 PMCID: PMC8679780 DOI: 10.1084/jem.20211336

Abstract

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.

© 2021 Lee et al.

Conflict of interest statement

Disclosures:   A. Patil reported personal fees from Combinatics Inc. outside the submitted work. No other disclosures were reported.

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