Life science
Medicine / Healthcare

Mechanism for the establishment of immunologicalmemoryLaboratory of Lymphocyte Differentiation, Immunology Frontier Research Center
SA Associate Professor Takeshi Inoue
Researchmap https://researchmap.jp/tak-inoue

Understanding the mechanism how our bodies respond to re-infection of pathogens, such as Influenza virus and SARS-CoV-2virus, is now one of the most important and urgent global issues
to be tackled. Successful vaccination, our best weapon against
these infectious diseases, relies on the induction of immunologicalmemory, but a still unanswered question is what drives the small
fraction of activated B cells to become quiescent memory B cells.
We found that a small population of germinal center (GC) B cellswith low metabolic activity and high expression of B cell receptors
serves as memory-prone precursor cells. Our achievement provides the underlying mechanism for the establishment of immunological memory, which will help to develop new vaccine design
strategies.

▍ Background & Results
Lymphocytes, such as B cells and T cells, are essential for immune responses against bacterial and viral infections. Especially,
memory B cells, which are generated during the first infection,quickly differentiate into plasma cells (antibody-secreting cells) andblock or eliminate antigens efficiently upon second infection (Fig.
1). Vaccination is a strategy to artificially induce the immunologicalmemory using this mechanism.
When exposed to antigens, such as viruses or bacteria, GC isgenerated in the secondary lymphoid organs including spleens
and lymph nodes. B cell fate decision occurs during GC reaction,
but it is still unclear how they are selected to differentiate into plasma cells, memory B cells, or to remain in the GC. In this study, we
have identified and characterized a small GC population of precursors for memory B cells, which express both a GC marker transcription factor Bcl6 and a memory B cell marker surface moleculeCD38. Through the analysis of these memory precursor B cells,
we found that the GC B cells with lower mTORC1 activity favor amemory B cell fate. In fact, a B cell-specific inhibition of mTORC1
activity during GC response resulted in increased memory B celldifferentiation. We also observed that memory precursor B cells
express higher surface B cell receptors (BCR) and a survival factor Bcl2 compared with other GC B cells. Our results suggested amodel in which weak T cell help from T cells together with provisionof an increased survival signal from BCR are the key for GC B cells
to adopt a memory B cell fate (Fig. 2).

novel universal vaccine design strategy.

Immunological memory:

quick and robust secondary response upon re-infection
Primary antibody response

Antibody amountLife science

AbstractFirstinfection

Secondary antibody response

Secondinfection

Plasma cellAntibodyNaïve
B cellMemory
B cellTime▍ Significance of the research and Future perspective
It is well known that upon HIV or influenza virus infection, we acquire the protective immunity against mutated viruses through theability of GC B cells to accumulate the somatic hypermutations inimmunoglobulin genes and to differentiate into long-lived memory
B cells. Our research on the mechanism of memory B cell generation may help to understand the reason for our requirements of annual influenza vaccination, and will provide basic data underlying aP a t e n t
Inoue, Takeshi; Shinnakasu, Ryo; Kawai, Chie et al. Exit from germinal center to become quiescent memory B cells depends on metabolic reprograming
and provision of a survival signal. J Exp Med, 2021; 218(1):e2020866. doi: 10.1084/jem.20200866.
http://lymph.ifrec.osaka-u.ac.jp/index.html
URL
https://resou.osaka-u.ac.jp/ja/story/2019/icfbo5
K e y w o r d B cell, antibody, vaccine, immunological memory
Tr e a t i s e