Class I major histocompatibility complex (MHC) molecules are common elements of the vertebrate immune system that present peptide antigens to cytolytic T-cells (CTL) and regulate natural killer (NK) cells. In humans and mice, MHC class I variability stems from codominant expression of multiple, polymorphic loci, and is the result of natural selection for diversification of the of the repertoire of presented peptides. Unexpectedly, the MHC class I genes of humans and mice have no one-to-one correspondence (orthology) and this pattern is reiterated in many other mammalian species. To study the evolution of identical class I genes in different species requires species more closely related than humans and mice. For this purpose the common chimpanzee and the human species provide an ideal system.
In Specific Aim 1, the structure and function of Patr-A, B and C polymorphism in the common chimpanzee will be defined and compared to alleles of the well characterized human HLA-A, B and C loci. This analysis will take place in the context of the chimpanzee CTL response to infection with human hepatitis C virus, and excellent model for the human disease and one for which there is preliminary evidence correlating class I type with disease resolution or chronicity. The differences between the MHC class I genes of humans and mice limit generalization of the principles underlying MHC class I variability and reveal the need for study of additional species, to test the paradigms developed from humans and/or mice. One such paradigm is the invariance of b2-microglobulin (b2m).
In Specific Aim 2, a polymorphism in b2m that segregates with populations of owl monkeys and which exerts conformational changes on the class I molecules with which it associates, will be defined. The substitution distinguishing the two forms of owl monkey b2m will be introduced into human b2m and the functional effects defined.
In Aim 3 the underlying cause of high b2m polymorphism in individual rainbow trout will be defined, and the hypothesis that trout b2m genes form a multigene family linked to the MHC tested. Preliminary results indicate low or no polymorphism for the trout classical MHC class I gene, a proposition that will be further investigated. Whereas the lineages of mammalian class I genes are shallow and shared by only the most closely related species, the results so far suggest that fish MHC class I genes have deep lineages shared by highly divergent species. This important difference will be explored in the context of the MHC class I genes of rainbow trout. The results to be obtained from these specific aims will provide new insights into different evolutionary pathways used by vertebrate populations to develop diversity in antigen presentation by MHC class I molecules.
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