The specific goal is to understand the structural basis of antigen presentation of classical (MHC class I, II) and non-classical (CD1, T10, T22) MHC or MHC-related antigens. Until recently, peptides from viral antigens, presented by MHC class I and II molecules were thought to be the primary antigens that activated antigens, presented by MHC class I and II molecules were though to be the primary antigens that activated alphabeta T cells. However, non-classical MHC-like molecules, such as CD1, can bind lipid and glycolipid antigens that are derived from the cell walls of bacterial pathogens. Hence, the immune system appears to have at least another branch that includes presentation of non-peptidic antigens by non-polymorphic molecules and provides a link between innate and acquired immunity. Other non-classical molecules, such as T10 and T22, appear to activate gammadelta T cells in the absence of external antigen and, hence, provide a further mechanism for regulation of the immune system. The specific goals in this proposal are to understand at the molecular level how MHC and MHC-like molecules can present peptides, glycopeptides, lipids and glycolipids to T cells in the cell-mediated immune system. The structural analysis of these MHC lipids and glycolipids to T cells in the cell-mediated immune system. The structural analysis of these MHC molecules in the context of recent T cell receptor-MHC structures can provide a framework to elucidate the molecules in the context of recent T cell receptor-MHC structures can provide a framework to elucidate the different responses to invasion of the host by microbial pathogens or suppression of tumors. The three- dimensional structures will be determined by x-ray crystallography.
The Specific Aims are as follows: 1. Crystal structures of mouse CD1.1 and human CD1d in complex with lipoglycans. 2. Crystal structures of human CD1b: Unliganded and with lipid or lipoglycan antigens. 3. Crystal structures of H-2T10 and H-2T22, non-classical antigen- independent T cell stimulators. 4. Crystal structures of naturally occurring mutants of mouse MHC class I H-2K/b. 5. Crystal structures of rat MHC RT1.A/a. 6. Crystal structures of MHC class II I-A/g7, an antigen implicated in autoimmune diabetes. 7. Crystal structures of MHC class II I-A/b complexes with antigenic peptides.
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