Recently, some experts have identified an essential part of the long-term memory of the immune system, providing useful new details for the design of better vaccines that are suitable for many diseases from COVID-19 to malaria. This new study, published in the Journal of Experimental Medicine, reveals the new role of the enzyme—TBK1 in determining the fate of memory B cells in the immune system.

The immune system is composed of many kinds of cells, but the two types of cells related to the research project of the University of Tokyo are leukocytes, called CD4+ follicular helper T cells and B cells. When the body recognizes the infection, the follicular helper T cells will release chemical signals, prompting immature B cells to learn and remember the pathogen to attack.

This process of T-B cell signal transmission and B cell training occurs in the temporary cell structure called the germinal center(GC) in the immune system organs, including the spleen, lymph nodes and tonsils. The memory B cells that develop in the germinal center remember the pathogen when it infects you for the first time, and then if it enters your body again, the mature, trained memory B cells will attack the pathogen by inducing the production of antibodies before it multiplies, so as to avoid your discomfort the second time.

However, how GCs are formed and regulated is not fully understand. In this study, the researchers identified the unexpected role of tank-bound kinase-1 (TBK1) as a key B cell intrinsic factor for GC formation. Using immune and malaria infection models, these scientists showed that despite the normal differentiation of Tfh cells, B cells lacking TBK1 failed to form GC, although some malaria-infected B-cell-specific TBK1-deficient mice can survive through GC-independent mechanisms.

In terms of mechanism, TBK1 phosphorylation increases in B cells during GC differentiation, and regulates the balance of IRF4/BCL6 expression by restricting CD40 and BCR activation through non-canonical NF-κB and AKTT308 signaling. In the absence of TBK1, CD40 and BCR signals synergistically enhance the expression of IRF4 in Pre-GC, resulting in BCL6 inhibition, so GC cannot be formed. Therefore, memory B cells produced by TBK1-deficient B cells cannot confer sterile immunity upon reinfection, indicating that TBK1 determines the fate of B cells to promote durable humoral immunity.

Over the years, the scientific community has determined the multiple roles of the TBK1 molecule. TBK1 is an enzyme that can change the activity of genes or other proteins by adding chemical markers through a process called phosphorylation. TBK1 has a well-known role in antiviral immunity. However, no research team has linked TBK1 to B cell fate and germinal centers.

Michelle S. J. Lee, the first author of the study and project assistant professor at the Institute of Medical Science at the University of Tokyo, explained that this is the first demonstration that TBK1 is essential for B cells to form germinal centers and produce high-quality, mature antibodies.

The researchers hope that with more basic knowledge of the remaining mysteries of the immune system, future vaccines can eventually be designed to produce longer-lasting immunity, which may not require multiple doses of vaccines. However, vaccine design is always complicated by the unique qualities of each pathogen and its mutant version, especially in the case of rapidly evolving pathogens, such as the virus SARS-CoV-2 that causes COVID-19.

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