Helper T cell recognition of antigen requires that the antigen be processed and presented by MHC class II expressing antigen presenting cells such as B cells and macrophages. For B cells, processing is initiated by antigen binding to the surface Ig. The antigen is internalized into acidic compartments, and proteolyzed to yield peptide fragments which bind to the class II molecules and are subsequently expressed on the cell surface. Processing and presentation of antigen is an early, critical event in the initiation of T cell-dependent antibody responses. The ability of B cells to produce a sufficient number of processed antigen-class II complexes and express these on their surface for a sufficient period of time will determine if helper T cells can be attracted and activated to provide the necessary helper functions. This proposal represents an approach to further delineate the cellular and molecular mechanisms underlying antigen processing and presentation in B cells. Over the last granting period an important advance was achieved in the isolation of subcellular vesicles in which processed-antigen class II complexes are assembled following Ig-mediated internalization of antigen. These vesicles represent extremely valuable material for subsequent study.
Four specific aims are proposed: 1) To continue the characterization of the processing vesicles in terms of their content and microenvironment using both biochemical and serological assays as well as immunoelectron microscopy; 2) To determine which surface molecules have access to these compartments; 3) To define the role of the surface Ig in facilitating and regulating antigen processing events and 4) To evaluate the effect of targeting antigen to IgD-expressing B cells in vivo. Knowledge gained through the proposed studies will be important in guiding the design of therapeutics which block the inappropriate processing or presentation of antigen as is likely to occur in autoimmune disease and in the design of peptide based vaccines.
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