The H-2 MHC class I system plays a crucial role in the cell mediated immune response against cell-associated foreign antigens. The long-term research objectives of this proposal are to continue studies to attempt to understand the basis and purpose of polymorphism and diversity in this system, and to determine the structural features of the MHC class I molecules important for their immunological function in the presentation of foreign antigens, i.e. MHC restriction. Studies on the question of polymorphism and diversity will be approached by continuing analyses of the mechanism of genetic recombination or gene conversion which has been shown to generate the in vivo MHC class I Kb mutants, a system which serves as a model for the mechanisms operating at the population level to generate diversity in the H-2 alleles. The details of class I gene conversion will be studied by molecular analysis of Kb molecules of additional in vivo bm variants, as well as through the study of an in vitro system in which DNA constructs will be utilized to measure interaction of class I H-2 DNA sequences. To analyze the structural features of class I molecules which are responsible for their immunological role, we propose to continue our studies of a series of somatic cell variants expressing altered Kb gene products. Such studies will be directed towards defining the target sites on the Kb molecule which are important for recognition by allogeneic T cells and by cytolytic T cells which recognize foreign antigens plus self MHC molecules. Where appropriate, specific Kbm mutant genes will be constructed by site directed mutagenesis for study in transfected cells. We will prepare large amounts of a few wild type and mutant Kb class I molecules for X-ray diffraction analysis to determine the three- dimensional structure.
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