Nonequivalence of Classical MHC Class I Loci in Ability to Direct Effective Antiviral Immunity

Kevin D Pavelko,Chella S David,Moses Rodriguez,Aaron J Johnson,Yanice Mendez-Fernandez,Michael J Hansen,Larry R Pease,Michael P Bell,Luis J Sigal

doi:10.1371/journal.ppat.1002541

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-2Kb gene are highly susceptible to persisting Theiler's virus infection within the CNS and subsequent demyelination, mice expressing the Db transgene clear the virus and are protected from demyelination. Remarkably, animals expressing a chimeric transgene, comprised primarily of Kb but encoding the peptide binding domain of Db, develop a robust anti viral CTL response yet fail to clear virus and develop significant demyelination. Differences in expression of the chimeric Kbα1α2Db gene (low) and Db (high) in the CNS of infected mice mirror expression levels of their endogenous H-2q 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.

Highlights

MHC class I antigen presenting molecules sample peptides generated intracellularly and present them on the surface of cells to CD8+ T cells bearing class I restricted T cell receptors [1,2,3]
A world wide effort has catalogued more than 6,300 classical HLA MHC I alleles in human populations, making these MHC loci among the best characterized polymorphic gene families
By expressing MHC I molecules capable of presenting viral antigens under regulatory determinants from different sister MHC I genes of the mouse, we address the hypothesis that locus-specific differences in the regulation of the homologous MHC I sister genes can determine whether alleles at any particular locus can effectively target protective immunity against virus infection

Summary

Introduction

MHC class I antigen presenting molecules sample peptides generated intracellularly and present them on the surface of cells to CD8+ T cells bearing class I restricted T cell receptors [1,2,3]. The MHC class I multigene families in mice and humans contain three genes encoding classical antigen presenting molecules [4], generally considered to have redundant functions. MHC polymorphism in South American Indian populations [9,10,11,12,13,14] provides a snapshot of the selective forces operating over the 15,000 years following the settling of the new world by their Asian ancestors [15].

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