TBK1 Essential for Germinal Center Formation During Infection

Research published today in the Journal of Experimental Medicine shows that TBK1 is essential in B cells to form germinal centers and produce high-quality, mature antibodies. TBK1 has well-known roles in antiviral immunity, but it previously had not been connected  to B cell fate and the germinal center.

After the body recognizes an infection, follicular helper T cells release chemical signals that cause immature B cells to learn and remember what pathogens to attack. This process of T-to-B cell signaling and B cell training occurs within the germinal center in organs of the immune system. Memory B cells developed within the germinal center memorize a pathogen the first time it infects you and then if it ever gets into your body again, the mature, trained memory B cells attack it by inducing antibody production before the pathogen can multiply, saving you from feeling sick a second time. 

“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,” explained first author Michelle S. J. Lee from the UTokyo Institute of Medical Science.

Lee and her team genetically modified mice that had nonfunctional TBK1 genes only in specific types of cells, primarily either B cells or CD4+ T cells. They then infected these 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 died sooner from the malaria infection than their normal peers. Additional experiments showed that the few mice who survived malaria with no TBK1 in their B cells were able to use other types of immune responses, but they can become reinfected. However, deleting TBK1 only from the CD4+ follicular helper T cells had no effect on the germinal centers or how the mice fared with a malaria infection.

Further analysis confirmed that without TBK1, many proteins in immature B cells had abnormal phosphorylation compared to normal immature B cells. For different genes, abnormal phosphorylation can cause either abnormal increases or decreases in activity. Researchers suspect that in B cells, TBK1 activity acts as an off switch for certain genes, essentially turning off genes that trap the B cells in their immature state.