MURINE TLA GENES--ORGANIZATION, EXPRESSION, REGULATION

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The class I family of genes is located in the major histocompatibility complex (MHC) of the mouse and encodes two major groups of protein products: the transplantation antigens and the non-classical or class lb antigens. The transplantation antigens are involved in the presentation of foreign antigens to cytotoxic T lymphocytes. The function of the class lb antigens is not known. Twenty-four class lb genes have been mapped to the Tla/Hmt region in the MHC of the BALB/c mouse. These genes are very divergent compared to the transplantation antigen genes, yet are highly conserved between different mouse strains. Some are expressed exclusively, or a highest levels, in lymphoid tissues. Several proteins encoded by the Tla/Hmt region genes have been identified. It has been proposed that the Tla/Hmt region genes have evolved to encode proteins that perform specialized functions in the mouse. The long-term objective of this research is to determine the function of the proteins encoded by the Tla/Hmt region genes. To achieve this goal, fundamental information regarding the organization, expression and regulation of these genes and their protein products is needed. In Aim I, we will clone the Tla/Hmt region in yeast artificial chromosomes. This will facilitate mapping of this region and will permit the identification of all class I genes residing in the region. In Aim II, antibodies will be raised against synthetic peptides derived from the predicted amino acid sequences of several class lb proteins and will be used to identify and characterize these proteins. The peptide antibodies and gene-specific oligonucleotide probes will be used to determine which tissues and which subpopulations of cells within those tissues, express individual class I genes. In Aim III, we will study the molecular mechanism involved in the regulation of one Tla/Hmt region gene that encodes the thymus-leukemia antigen. Cis-acting elements and proteins that interact with these elements will be identified using functional assays and state-or-the-art molecular biological techniques. The results of these studies will provide a basis for future studies to determine the functions may lead to further definition of the complex cellular interactions involved in the vertebrate immune response.