The human leukocyte common antigens (LCAs) are a family of related high molecular weight (180-240kD) cell-surface glycoproteins found in lymphocytes and other hematopoietic cells. Up to eight isoforms of LCAs are generated from a single gene by differential usage of three exons. Various LCA isoforms have been implicated in an array of effector and regulatory functions of lymphocytes, such as cytotoxicity and proliferation. The importance of LCAs in the regulation of immune circuitry was suggested by the following findings: the LCAs with the 2H4 epitope are expressed on the T4+ cells that induce the activity of T8+ suppressor cells, while the LCAs with another epitope, UCHLl, is expressed exclusively on the T4+ cells that induce immunoglobulin production by B cells. Furthermore, markedly reduced expression of the 2H4 epitope on the T4+ cells from patients of progressive multiple sclerosis and active systemic lupus erythematosus has suggested an important role of the LCAs in these autoimmune diseases. Our long-term objective is to understand the molecular basis of the differentiation and regulation of T lymphocyte functions through the characterization of the structure, function, and regulation of the LCAs, using a combination of techniques of molecular biology, biochemistry, and cellular immunology.
The specific aims of this proposal are: 1) Isolation and characterization of the structure of the human leukocyte common antigen gene. 2) Analysis of the regulation of human LCA gene expression The activities of the regulatory elements of LCA gene expression, such as promoters and enhancers, will be identified and characterized. The developmental control of differential mRNA splicing that produces diverse forms of the LCA molecules will be studied both in vivo and in vitro. 3) The function of the human LCA molecules will be studied. Cell lines that express individual isoforms of LCA will be constructed, and used to generate anti-LCA antibodies that can distinguish individual isoforms. The antibodies will be used to study the biochemical mechanism of the regulatory and effector functions of the individual LCA isoforms. The potential ligand of the LCAs will be identified. 4) The LCA-related proteins and their genes will be characterized. The cDNA clones encoding LCA-related proteins will be isolated, and structures determined. Antibodies against the LCA-related proteins will be generated and used to identify the gene products and to study their functions.
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