Allelic and isotopyc differences affecting H2-M functions

H2-M is a nonconventional major histocompatibility complex (MHC) class II molecule that is essential for peptide loading onto conventional class II molecules. H-2b haplotype mice lacking H2-M activity are defective in class II peptide loading, antigen presentation, and CD4+ T cell maturation. Recent experiments suggest that highly polymorphic MHC class II alleles differ in their dependency on H2-M activities. However, these observations were made using heterologous systems influenced by numerous parameters. A major aim of this project is to create via a gene targeting strategy H2-M mutant mouse strains carrying the H-2k and H-2d haplotypes. Their phenotypic defects will be compared to those previously described for the H-2b allele. In addition, overlapping and/or unique functions contributed by the two alternative unequally expressed H2-M beta chains, beta1 and beta2 will be tested. To examine H2-Mbeta2 specific contributions, we plan to generate mutant mice carrying a loss of function mutation at the H2-Mb2 locus and thus exclusively expressing the H2-Mbeta1 product. Their phenotypic defects will be compared to those previously described for H2-M alpha chain mutants.