The current goal of this longstanding research program is to define the role of FDC as antigen-handling accessory cells in the induction and maintenance of secondary antibody responses. Previous work by this investigator and others has shown that antigen-antibody complexes can persist for months on the surface of FDC in spleen and lymph nodes where they serve as an antigen reservoir to maintain antibody formation. It is thought that antigen is released by FDC as immunogenic cell fragments called iccosomes that are taken up by antigen-specific B-cells. These studies are based on work in the previous project period showing that Ag-Ab complexes, which are normally poorly immunogenic in vitro, provoke potent in vitro secondary antibody responses upon addition of purified FDC. The investigator proposes that FDC have two functions that can be studied in this in vitro system: they allow antigen to bind to antigen receptors and activate Ag-specific B-cells in the presence of a large excess of specific antibody, and they provide accessory signals that enhance B-cell proliferation and survival. The proposed experiments will be done using in vitro secondary antibody responses of purified cell types from mouse spleen and lymph node and human peripheral blood (PBL) and tonsil. FDC will be compared with class II positive FDCs and macrophages and fibroblasts transfected with ICAM-1, Fc receptor, and complement receptor for their ability to provide these Ag-handling and accessory cell functions in short-and long-term cultures. The experiments on FDC-mediated costimulation are designed to test the hypothesis that fragments of C3 fixed to FDC or to antigen-antibody complexes on the FDC surface deliver the costimulatory signals via CR2 complement receptors on B-cells, which are part of the CD19/CR2/TAPA-1 complex known to potentiate activating signals through the antigen receptor. The roles of CR2 and Fc receptors in the antigen-handling functions of FDC will be investigated. Finally, the apparent ability of FDC to protect B-cells from apoptosis and maintain lymphocyte in culture for weeks will be studied.
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