Japanese experts have identified a fundamental part of the immune system’s long-term memory, providing a new detail useful in the pursuit of the design of better vaccines against diseases ranging from COVID-19 to malaria. The research, published in the Journal of Experimental Medicine, reveals a new role for the TBK1 enzyme in determining the fate of memory B cells in the immune system.
The immune system is made up of many types of cells, but the two types relevant to this University of Tokyo research project are white blood cells called CD4 + follicular helper T cells and B cells. After the body recognizes an infection. , follicular helper T cells release chemical signals that cause immature B cells to learn and remember which pathogens to attack. This process of T-to-B cell signaling and B-cell entrainment occurs within a temporary cellular structure called the germinal center in organs of the immune system, including the spleen, lymph nodes, and tonsils. The memory B cells developed within the germinal center memorize a pathogen the first time it infects you, and then if it ever re-enters your body, the mature and trained memory B cells attack it by inducing the production of antibody before the pathogen can multiply, thus preventing you from feeling sick a second time.
“One of the goals of vaccination is to produce high-quality memory B cells for long-lasting antibody production,” said project assistant professor Michelle SJ Lee of the UTokyo Institute of Medical Science, first author of the recent publication.
“There are many factors to consider when designing vaccines for long-lasting immunity, so we shouldn’t just focus on the germinal center alone. But if you don’t have a functioning germ center, then you will be very susceptible to reinfection, ”Lee said.
However, there is no limit to the number of times you can be bitten by mosquitoes and re-infected with the malaria parasite. Somehow, the malaria parasites escape memory B cells. Although children are more likely to die from malaria than adults, some people can become seriously ill despite a number of previous malaria infections.
This ability of the parasite to prevent and escape efficient B cells is what makes malaria such a pathogen of interest to Professor Cevayir Coban, who heads the Division of Malaria Immunology at the UTokyo Institute of Medical Science and is the latest author of the research paper with Lee and colleagues. at Osaka University.
“We want to understand the fundamentals of the natural immune response. Whatever we do, we should aim to ultimately benefit malaria patients, ”Coban said. “The COVID-19 pandemic has drawn global attention to infectious diseases and interest in vaccine design, so we have a chance to renew attention to neglected diseases like malaria,” he said. she continued.
For many years, the scientific community has identified a wide range of roles for the TBK1 molecule, an enzyme that can alter the activity of genes or other proteins by adding chemical markers, through a process called phosphorylation. TBK1 has well-known roles in antiviral immunity. However, no research group had connected TBK1 to B cell fate and germinal center.
The researchers genetically engineered mice that had nonfunctioning TBK1 genes only in specific cell types, mostly B cells or CD4 + T cells. This cell-type-specific knockout of TBK1 gives researchers a clearer idea of what a gene with many works is doing in different cells in the body. Coban, Lee, and their colleagues infected these engineered mice and healthy adult mice with the malaria parasite, observed their health, and then examined samples of their spleen and lymph nodes.
Microscopic images revealed that germ centers only form in mice that have functional TBK1 in their B cells. Mice without TBK1 in their B cells were more likely to die and die sooner from malaria infection than their normal peers. Further experiments showed that the few mice that survived malaria without TBK1 in their B cells were able to use other types of immune responses, but they can be re-infected.
However, deletion of TBK1 only from CD4 + follicular helper T cells had no effect on the germinal centers or on the way the mice suffered from malaria infection.
Further analysis confirmed that without TBK1, many proteins in immature B cells exhibited abnormal phosphorylation compared to normal immature B cells. For different genes, abnormal phosphorylation can cause abnormal increases or decreases in activity. Researchers suspect that in B cells, TBK1 activity acts as a switch for certain genes, essentially turning off genes that trap B cells in their immature state.
“This is the first time that TBK1 has been shown to be essential in B cells for forming germinal centers and producing high quality mature antibodies,” said Lee.
The researchers hope that with more fundamental knowledge of the remaining mysteries of the immune system, future vaccines can be designed to produce longer lasting immunity, potentially without the need for multiple doses of the vaccine. However, the design of a vaccine will always be complicated by the unique qualities of each pathogen and its mutated versions, especially in the case of rapidly evolving pathogens like Sars-CoV-2, the original virus. of COVID-19.
“For now, we can at least say that an effective vaccine designed to produce long-lasting protective immunity should not reduce the activity of TBK1 in B cells,” Coban said.