Scientists find new details about how immune system builds long-term
memory
Mouse study identifies intrinsic TBK1 enzyme as essential for determining
B cell fate

Date:
December 16, 2021
Source:
University of Tokyo
Summary:
Experts in Japan have identified a fundamental part of the immune
system's long-term memory, providing a useful new detail in the
pursuit to design better vaccines for diseases, ranging from
COVID-19 to malaria.



FULL STORY ========================================================================== Experts in Japan have identified a fundamental part of the immune system's long-term memory, providing a useful new detail in the pursuit to design
better vaccines for diseases, ranging from COVID-19 to malaria. The
research, published in the Journal of Experimental Medicine, reveals
a new role for the enzyme TBK1 in deciding the fate of immune system
memory B cells.


==========================================================================
The immune system is made of many cell types, but the two types relevant
for 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, the 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 a temporary cell structure called the germinal center
in organs of the immune system, including the spleen, lymph nodes and
tonsils. 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.

"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 from 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 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.

However, there is no limit to the number of times you can be bitten
by mosquitoes and reinfected by the malaria parasite. Somehow, malaria parasites escape memory B cells. Although children are more likely to
die from malaria than adults, some people can become severely ill despite
any number of previous malaria infections.

This ability of the parasite to prevent and evade effective B cells is
what makes malaria an interesting pathogen for Professor Cevayir Coban,
who leads the Division of Malaria Immunology at the UTokyo Institute of
Medical Science and is last author of the research paper with Lee and collaborators at Osaka University.



==========================================================================
"We want to understand the fundamentals of the natural immune response.

Whatever we do should aim to eventually benefit malaria patients,"
said Coban.

"The COVID-19 pandemic brought global attention to infectious diseases
and interest in vaccine design, so we have a chance to renew the focus
on neglected diseases like malaria," she continued.

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, no research
group had connected TBK1 to B cell fate and the germinal center.

Researchers genetically modified mice that had nonfunctional TBK1
genes only in specific types of cells, primarily either B cells or CD4+
T cells. This cell type-specific knockout of TBK1 gives researchers a
clearer idea of what a gene with many jobs is doing in different cells
of the body. Coban, Lee and their colleagues 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.

"This is the first time to show TBK1 is essential in B cells to form the germinal centers and produce high-quality, mature antibodies," said Lee.

Researchers are hopeful that eventually, with more fundamental knowledge
about the remaining mysteries of the immune system, future vaccines
can be designed to produce longer-lasting immunity, potentially without
needing multiple doses of vaccine. However, vaccine design 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 virus causing COVID-19.

"For now, we can at least say that an effective vaccine tailored to
produce long-lasting protective immunity should not reduce TBK1 activity
in B cells," said Coban.

========================================================================== Story Source: Materials provided by University_of_Tokyo. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Michelle S.J. Lee, Takeshi Inoue, Wataru Ise, Julia Matsuo-Dapaah,
James
B. Wing, Burcu Temizoz, Kouji Kobiyama, Tomoya Hayashi, Ashwini
Patil, Shimon Sakaguchi, A. Katharina Simon, Jelena S. Bezbradica,
Satoru Nagatoishi, Kouhei Tsumoto, Jun-Ichiro Inoue, Shizuo Akira,
Tomohiro Kurosaki, Ken J. Ishii, Cevayir Coban. B cell-intrinsic
TBK1 is essential for germinal center formation during infection
and vaccination in mice.

Journal of Experimental Medicine, 2022; 219 (2) DOI:
10.1084/jem.20211336 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211215113223.htm

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