Life science
Medical & healthcare, Drug development

Identification and developmental regulation of long-lived
plasma cells
Regulation of Host Defense Team, Center for Infectious Disease Education and Research
Professor Wataru Ise
https://researchmap.jp/wataruise?lang=en

Life science

AbstractLong-term survival of plasma cells is essential for durable humoral responses and protection from viral infection. However, little
is known about how newly-generated plasma cells in lymphoidtissues can achieve longevity for months or years. Here, we generated experimental system, in which plasma cells can be inducibly
and irreversibly labeled so can be “time-stampled”. We analyzed
plasma cells survival for a year and found molecular markers thatallow us to distinguish short-lived and long-lived plasma cells (LLPCs).
Furthermore, We found how LLPCs are generated or where LLPCs
are abundant in tissues. Finally, we demonstrated that LLPCs aresessile in survival niches. Our results will help to develop new vaccines that target efficient induction of LLPCs.

▍ Background & Results
Neutralizing antibodies induced by vaccination are essentialfrom viral infection. Antibodies are produced by terminally differentiated B cells, called plasma cells. A small fraction of plasma
cells generated upon infection or vaccination survive for months
or years in the survival niches in bone marrow (BM) or mucosal
tissues, continue to produce neutralizing antibodies, and contribute to long-term protection. We’ve developed a new experimental
system, in which the fate of plasma cells can be “time-stamped”,
and analyzed plasma cell survival over one year. Newly generated
plasma cells were uniformly B220hi MHC-IIhi with short-half lived
but were progressively differentiated into B220lo MHC-IIlo long-lived
plasma cells (LLPCs). Such LLPCs were found in BM, spleen, orlamina propria in small intestine, but plasma cells survived longer
in BM than other tissues. We also found that in the BM, germinal
center (GC)-independent and GC-dependent plasma cells decayed similarly upon antigen engagement, and both entered theB220lo MHC-IIlo LLPC pool. Intravital imaging analysis revealed thatcompared with B220hi MHC-IIhi plasma cells, LLPCs were more
immobilized in the BM niches and showed better survival potential.
Thus, our results suggest that the adhesion status of BM plasma
cells is dynamically altered during their differentiation and is associated with provision of survival signals.

▍ Significance of the research and Future perspective
Our new experimental system allowed us to identify molecularmarkers of LLPCs that can distinguish from short lived plasma
cells. We will isolate LLPCs from distinct tissues and analyze gene
expression in more detail to clarify molecular mechanisms underlying long-term survival of plasma cells during infection or vaccination. Such studies will lead to development of new vaccine that canimprove durability of antibody response.

P a t e n t
Tr e a t i s e

Koike, Takuya et al. Progressive differentiation towards the long-lived plasma cell compartment in the bone marrow. Journal of Experimental Medicine.
2023, 220 (2):e20221717. doi: 10.1084/jem.20221717

URL
K e y w o r d antibody, vaccine, plasma cell, infectious disease