Role of BAFFR in antigen-specific B1b cell persistence

项目总结。

Project Summary. Infectious diseases are the leading cause of death worldwide and vaccination is the most effective means of prevention. Vaccination results in long-term resistance to infections due to the generation of immunological memory, for which persistence of high numbers of antigen-specific B cells is essential. The magnitude of anamnestic responses is directly proportional to the size of the antigen-specific memory B cell pool. T cell- independent B cell responses are much more rapid than the T cell-dependent responses and play a critical role in combating a variety of infections, in particular those caused by encapsulated bacterial pathogens. Pure polysaccharides isolated from encapsulated bacteria are commonly referred to as T cell-independent antigens and induce primary antibody responses by B cell antigen receptor cross-linking. These antigens do not induce heightened secondary antibody responses upon re-immunization, suggesting that T cell-independent responses do not generate B cell memory. Using Borrelia hermsii infection, an experimental bacterial system that engages B cell antigen receptor signaling in addition to other immunostimulatory pathways, we discovered a novel function for B1b cells in T cell-independent B cell memory. Specifically, we found that B1b cells expand concurrently with the resolution of B. hermsii bacteremia and persist for long time periods. B1b cells from convalescent mice but not from na¿ve mice generate a heightened antibody response and confer immunity, indicating that the protective response corresponds to antigen-specific B1b cell expansion and persistence, a key attribute of B cell memory. Additionally, using Enterobacter cloacae that expresses the polysaccharide antigen, ¿1-3 dextran it has been shown that antigen-specific B1b cells that expand in the initial phase of antigen encounter persist for long time periods and generate robust anamnestic responses in a T cell- independent manner. Although these bacterial systems demonstrate that B1b cell memory responses can be generated in a T cell-independent manner, the molecular mechanism governing the long-term maintenance of the memory B1b cells is unknown. B cell activating factor (BAFF), also known as B Lymphocyte Stimulator (BLyS) plays an important role in mature B cell survival and function through its receptors BAFFR and TACI. We found that in the B. hermsii infection system efficient B cell responses depend on BAFF and BAFFR but not TACI. Furthermore, we found that B1b cells that expand and persist in response to B. hermsii infection or E. cloacae immunization express higher levels of BAFFR compared to naive B1b cells. Since higher levels of BAFFR expression on B1b cells can impart a BAFF-dependent competitive survival advantage over naive B1b cells under BAFF-limited conditions, we hypothesize that bacteria-stimulated B1b cells persist for long time periods through BAFFR upregulation. Determination of the role of BAFFR in the long-term maintenance of B1b cells will provide novel approaches for the generation of effective vaccines.