title: Nonequivalence of classical MHC class I loci in ability to direct effective antiviral immunity.
abstract: Structural diversity in the peptide binding sites of the redundant classical MHC antigen presenting molecules is strongly selected in humans and mice. Although the encoded antigen presenting molecules overlap in antigen presenting function, differences in polymorphism at the MHC I A, B and C loci in humans and higher primates indicate these loci are not functionally equivalent. The structural basis of these differences is not known. We hypothesize that classical class I loci differ in their ability to direct effective immunity against intracellular pathogens. Using a picornavirus infection model and chimeric H-2 transgenes, we examined locus specific functional determinants distinguishing the ability of class I sister genes to direct effective anti viral immunity. Whereas, parental FVB and transgenic FVB mice expressing the H-2K(b) gene are highly susceptible to persisting Theiler's virus infection within the CNS and subsequent demyelination, mice expressing the D(b) transgene clear the virus and are protected from demyelination. Remarkably, animals expressing a chimeric transgene, comprised primarily of K(b) but encoding the peptide binding domain of D(b), develop a robust anti viral CTL response yet fail to clear virus and develop significant demyelination. Differences in expression of the chimeric K(b)α1α2D(b) gene (low) and D(b) (high) in the CNS of infected mice mirror expression levels of their endogenous H-2(q) counterparts in FVB mice. These findings demonstrate that locus specific elements other than those specifying peptide binding and T cell receptor interaction can determine ability to clear virus infection. This finding provides a basis for understanding locus-specific differences in MHC polymorphism, characterized best in human populations.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Pavelko
authors.forename: Yanice
authors.initials: Y
authors.lastname: Mendez-Fernandez
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hansen
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Larry R
authors.initials: LR
authors.lastname: Pease
mesh_terms: D000818:Animals; D004526:Efficiency; D005805:Genes, MHC Class I / Q000502:physiology*; D056426:Genetic Loci / Q000502:physiology*; D006183:H-2 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008958:Models, Molecular; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology; D014780:Viruses / Q000276:immunology*
chemical_list: D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D