Identification and characterization of cellular mechanisms which selectively cont

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DESCRIPTION (provided by applicant): Cytotoxic CD8+ T cells are defensive cells within the body that are responsible for eliminating self cells that have become infected with an intracellular microbe, such as a virus. To prevent elimination of otherwise healthy cells, cytotoxic T cells must first recognize a fragment of the disease-specific protein bound to an MHC class I molecule, which will be displayed on the surface of the diseased cell. While the peptide fragments may be derived due to the natural turnover of proteins within the cell, peptide-MHC complexes can be detected on the cell surface rapidly after the induction of protein antigen synthesis. This has led to the defective ribosomal product (or DRiP) hypothesis which states that a subset of newly synthesized protein will be defective and immediately degraded within the cell. This work will test the hypothesis that cells have a specific mechanism for generating protein antigens and will use a newly described assay that can segregate the sources of antigenic peptides into true DRiPs and peptides derived from the natural turnover of proteins. This assay has already indentified several chemicals and gene products which can selectively eliminate DRiP antigen presentation. These targets will be the starting point to identify the cellular mechanism(s) that govern how DRiPs are generated and targeted for antigen presentation. The ubiquitin conjugation and removal elements of the cell will be specifically monitored as they have been implicated in antigen presentation. The results of this work will have important implications for the development of vaccines and therapies that are designed to elicit cytotoxic T cell responses to a variety of diseases. PUBLIC HEALTH RELEVANCE (provided by applicant): Cytotoxic T cells are responsible for eliminating virally infected cells within the body. T cells are remarkably specific in that they recognize fragments of viral proteins bound to cellular MHC molecules on the cell surface. The purpose of this work is to determine how the cells generate these protein fragments following viral infection.