Several recent reports have documented the ability of MHC class Ib molecules to present peptide antigens to T cells, be it killer or helper T cells with alpha-beta or gamma-delta receptors. The immune responses studied do include protection against bacterial infection, and the supposed lack of polymorphism of class Ib genes make them preferred targets for peptide vaccines. However, the relative importance of MHC class Ib vs. Ia molecules in defense against opportunistic bacterial infections remains to be established: how many are functional? which ones are predominantly expressed at points of bacterial entry, such as the lung and gut epithelia? are they indeed specialized for bacterial antigens? are they as conserved as claimed? how big is the repertoire of peptides they can present? and would their absence severely compromise the host? Mouse class Ib genes have been most extensively characterized in the b and d haplotypes, where cosmid clones define 10 genes in the Q, 15-20 in the T, and 8 in the M region; yeast artificial chromosomes (YACs) newly isolated in the PI's laboratory has added 12 new class I genes to the M region. But even in these familiar haplotypes, the physical map has large gaps that may hold additional genes, class Ib or other, and the order of the cosmid clusters is unknown. Little information is available on the number and order of class Ib genes in other haplotypes, such as a and f, which represent major, functionally distinct alleles in contrast to the rather similar b and d haplotypes.
The aim of this proposal is to complete the physical map of the Q/T/M regions, to determine which class Ib genes are expressed where, and to assess the extent of polymorphism and divergence of thee genes, including whether alleles of pseudogenes might be expressed in other haplotypes, including those of Mus spretus and M. m. castaneus, which are separated by 0.3 to l million years of evolution from laboratory mice. Once completed, this new picture of the distal MHC will clarify the evolution of the class Ib genes, the selective forces that have shaped them, and their functional significance relative to class Ia genes.
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