Scientists from the University of Tokyo Institute of Medical Science report they have discovered a new role for the enzyme TBK1. Their mouse study revealed that the enzyme helps decide the fate of immune system memory B cells.
The findings are published in the Journal of Experimental Medicine in a paper titled, “B cell–intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice.”
“The germinal center (GC) is a site where somatic hypermutation and clonal selection are coupled for antibody affinity maturation against infections,” the researchers wrote. “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.”
“A goal of vaccination is to produce high-quality memory B cells for long-lasting antibody production,” said project assistant professor Michelle S. J. Lee, PhD, from the University of Tokyo Institute of Medical Science.
“There are many factors to consider when designing vaccines for long-lasting immunity, so we should not focus only on the germinal center alone. But if you don’t have a functional germinal center, then you will be very susceptible to reinfection,” said Lee.
The researchers sought to determine the fundamentals of the natural immune response.
Over many years, the scientific community has identified a wide range of roles for the molecule TBK1, an enzyme that can alter the activity of genes or other proteins by adding chemical tags, through a process called phosphorylation. TBK1 has well-known roles in antiviral immunity. However, this is the first time researchers have made the connection of TBK1 to B cell fate and the germinal center.
The researchers genetically modified mice that had nonfunctional TBK1 genes only in specific types of cells, primarily either B cells or CD4+ T cells. The researchers then infected the modified mice and healthy adult mice with the malaria parasite, observed their health, and then examined samples of their spleens and lymph nodes.
Microscopy images revealed that germinal centers only form in mice that have functional TBK1 in their B cells. Mice with no TBK1 in their B cells were more likely to die and die sooner from the malaria infection than their peers.
Further observation revealed that without TBK1, many proteins in immature B cells had abnormal phosphorylation compared to normal immature B cells.
“This is the first time to show TBK1 is essential in B cells to form the germinal centers and produce high-quality, mature antibodies,” explained Lee.
The researchers are hopeful that further studies will lead to the development of future vaccines to produce longer-lasting immunity, potentially without needing multiple doses of vaccine.
