Class I histocompatibility antigens are polymorphic cell surface glycoproteins encoded by a series of genes within the major histocompatibility complex. The products of the HLA-A,-B,-C loci in man, and the H-2K,-D,-L loci in the mouse, are known to mediate interactions between cytotoxic T lymphocytes and target cell surfaces. The funcitons of the murine Qa and T1a region products and their presumed human homologues are understood poorly, if at all. Typically, class I molecules are integral membrane proteins, and are only understood functionally in this capacity. However a variety of soluble and/or serum forums has been detected, including HLA-A and -B products in man, and a Qa region product in the mouse. It is the primary intent of the proposed research to document examples of human class I antigen secretion, to determine the structure of the secreted molecules and to characterize both the mechanism and regulation of secretation. These studies should allow insights into potential biological roles for such molecules in vivo. Specific approaches will be as follows: (l) A mutant B cell line which secretes HLA-A2 due to altered RNA splicing will be studied. The precise mutation will be identified through the structural analysis of genomic clones from the parent and mutant cell lines. (2) Evidence that a related alternative splicing mechanism is operative in vivo willbe explored further. A wide variety of cell types will be studied. Protein products will be characterized. mRNA structure will be assessed by Northern analysis using oligonucleodtide probes, and by obtaining and characterizing cDNA clones. Evidence for regulation will be sought. (3) The potential of alternative splicing as a genral mechanism for producing functional heterogeneity of class I antigens will be explored. Specific oligonucleotide probes will be used to assess patterns of splicing in a wide variety of cell types. (4) A human homologue of the murine Qa-encoded, secreted class I molecule will be sought. Selected cDNA libraries will be screened to detect clones encoding non-HLA-A,-B,-C class I molecules. Transfected non-HLA-A,-B,-C class I genomic clones will be assayed for expression of secreted and membrane bound molecules. The structure and regulation of any gene so identified will be analyzed in detail.
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