Class I major histocompatibility molecules function as receptors that bind immunogenic peptides and present them to cytotoxic T lymphocytes. Recent studies by us and others have shown that the expression of certain class I molecules (e.g., Ld), or class I molecules on certain mutant cell lines (e.g., RMA.S), can be specifically increased by culture with peptide ligands. These findings provide clear evidence that class I molecules have accessible ligand binding sites. Exploiting this accessibility, we have: 1) developed a class I-ligand binding assay, 2) discovered a monoclonal antibody specific for non-ligand associated class I molecules, and 3) established an extensive panel of peptide-specific, class I-restricted CTL clones. Using these unique resources we now propose to quantitate the specificity and physical/chemical properties of the interaction of various class I molecules with their respective ligands. Furthermore, the role of peptide ligand will be defined in the folding and assembly of nascent class I molecules as well as the stabilization of surface class I molecules. With focus on recognition of Ld class I molecules, structure-function analyses will also be performed. New and existing mutant molecules will be analyzed to identify key residues involved in the interaction of the Ld molecule with ligand, T cell receptor, beta2m and monoclonal antibodies that discriminate peptide association. The information obtained in this study will precisely define the role of peptide ligand in the expression of class I molecules. Such knowledge is paramount to our complete understanding of the function of class I molecules in the immune surveillance against virus-infected and malignant cells.
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