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Immunological Memory

Research Area
T-cell dependent antigen exposure leads to the formation of short-lived antibody secreting plasma cells and germinal center (GC) B cells which undergo somatic mutations and isotype switching. GC B cells are believed to generate memory B cells and long-lived plasma cells under the antigen- driven selection, however, to our knowledge, no direct evidence proves this possibility. Memory B cells show a unique morphology and phenotype and acquire several intrinsic properties that differ from other B cell stages, such as longevity, preferential localization in the antigen draining sites, and rapid response to antigen reexposure by differentiating into plasma cells. However, the mechanisms underlying memory B cell development, maintenance, and terminal differentiation remain obscure. Our intention is to ascertain the origin of memory B cells and the mechanisms underlying memory B cell development, maintenance, and signaling responsible for terminal differentiation. To approach these fundamental problems, we are analyzing the dynamics of memory B cells by virtue of FACS with a seven color system and characterizing the genes that are highly expressed in memory B cells.


Background

We suggest that memory B cells are generated within 3 wk after immunization. We observed that CD95(Fas) regulates the selection of the memory B cell repertoire (Immunity 2001; see Fig.1); however, unfortunately, the underlying mechanism remains obscure. We suggest that memory B cells are susceptible to apoptosis at terminal differentiation, owing to their hyper-reactivity to antigen reexposure, whereas a Ras-mediated cascade may rescue the cell death (Immunity 2005; see Fig.1). These results support the view that memory B cells have a unique signaling module, distinct from other B cell stages (see blow). Finally regarding the pathway of memory B cell generation, our collaborative work with Dr. Tokuhisaユs group at Chiba University have provided the possibility memory B cells are generated at the early immune response, probably prior to the generation of apoptosis susceptible germinal centers at terminal differentiation (Immunity 2002, Int. Immunol. 2005).