Abstract of the paper
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 both immunization and malaria infection models, we show that TBK1-deficient B cells failed to enter GC reaction despite the induction of normal TFH differentiation. Mechanistically, TBK1 is increasingly phosphorylated in B cells during GC differentiation and fine tunes the balance between IRF4 and BCL6 expression by limiting CD40 and BCR activation through non-canonical NF-κB and AKTT308 signaling. In the absence of B cell intrinsic TBK1, CD40 and BCR signaling uncontrollably upregulated IRF4 expression in Pre-GC leading to the suppression of BCL6, resulting in the failure to form GC to mount high affinity, and antigen-specific antibodies. As a result, memory B cells generated in the absence of TBK1 fail to confer sterile immunity upon re-infection. These findings have crucial implications for tailoring vaccines to produce long lasting protective humoral immunity.
Press release
B-cell signaling factors essential for immunological memory in infections and vaccines discovered
Description
Journal of Experimental Medicine Article 
Published Article
"B-cell signaling factors essential for immunological memory in infections and vaccines discovered"
Journal of Experimental Medicine online December 15, 2021 doi: 10.1084/jem.20211336
Authors: Michelle S. J. Lee1,12, Takeshi Inoue2, Wataru Ise2, Julia Matsuo-Dapaah1, James B. Wing3,4, Burcu Temizoz5, Kouji Kobiyama5, Tomoya Hayashi5, Ashwini Patil6, Shimon Sakaguchi7, A. Katharina Simon8, Jelena S. Bezbradica8, Satoru Nagatoishi9, Kouhei Tsumoto9,10, Jun-Ichiro Inoue9, Shizuo Akira11, Tomohiro Kurosaki2, Ken J. Ishii5,11,12, Cevayir Coban1,11,12*
1Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
2Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
3Laboratory of Human Immunology (Single Cell Immunology), IFReC, Osaka University, Osaka, Japan
4Human Single Cell Immunology Team, Center for infectious Disease Education and Research (CiDER), Osaka University, Osaka, Japan
5Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
6Combinatics Inc., Tokyo, Japan
7Laboratory of Experimental Immunology, IFReC, Osaka University, Osaka, Japan
8The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
9Research Platform Office, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
10Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
11IFReC, Osaka University, Osaka, Japan
12International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
*Correspondence: ccoban@ims.u-tokyo.ac.jp (C.C.)
1Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
2Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
3Laboratory of Human Immunology (Single Cell Immunology), IFReC, Osaka University, Osaka, Japan
4Human Single Cell Immunology Team, Center for infectious Disease Education and Research (CiDER), Osaka University, Osaka, Japan
5Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
6Combinatics Inc., Tokyo, Japan
7Laboratory of Experimental Immunology, IFReC, Osaka University, Osaka, Japan
8The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
9Research Platform Office, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
10Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
11IFReC, Osaka University, Osaka, Japan
12International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
*Correspondence: ccoban@ims.u-tokyo.ac.jp (C.C.)