Cmv4, a New Locus Linked to the NK Cell Gene Complex, Controls Innate Resistance to Cytomegalovirus in Wild-Derived Mice

Abstract

CMV can cause life-threatening disease in immunodeficient hosts. Experimental infection in mice has revealed that the genetically determined natural resistance to murine CMV (MCMV) may be mediated either by direct recognition between the NK receptor Ly49H and the pathogen-encoded glycoprotein m157 or by epistatic interaction between Ly49P and the host MHC H-2Dk. Using stocks of wild-derived inbred mice as a source of genetic diversity, we found that PWK/Pas (PWK) mice were naturally resistant to MCMV. Depletion of NK cells subverted the resistance. Analysis of backcrosses to susceptible BALB/c mice revealed that the phenotype was controlled by a major dominant locus effect linked to the NK gene complex. Haplotype analysis of 41 polymorphic markers in the Ly49h region suggested that PWK mice may share a common ancestral origin with C57BL/6 mice; in the latter, MCMV resistance is dependent on Ly49H-m157 interactions. Nevertheless, PWK mice retained viral resistance against m157-defective mutant MCMV. These results demonstrate the presence of yet another NK cell-dependent viral resistance mechanism, named Cmv4, which most likely encodes for a new NK activating receptor. Identification of Cmv4 will expand our understanding of the specificity of the innate recognition of infection by NK cells.

Ly49h-Deficient C57BL/6 Mice: A New Mouse Cytomegalovirus-Susceptible Model Remains Resistant to Unrelated Pathogens Controlled by the NK Gene Complex

“…NK cell activity was determined in NK cell cytotoxicity assays as previously described (34). Briefly, freshly explanted NK cells were washed with PBS, resuspended in complete RPMI 1640 medium, and seeded into wells of a 96-well, round-bottom microtiter plate in graded dilutions to obtain the desired E:T ratios.…”

Immune evasion of natural killer cells by viruses

“…Altogether, by its specificity for MHC class I allele and viral protein, Ly49P represents another highly specific mechanism of NK cell-mediated control. An additional locus, Cmv4, is also suggested to encode an NK cell activating receptor and mediate MCMV resistance in PWK mice [66].…”

Identification of Mouse Cytomegalovirus Resistance Loci by ENU Mutagenesis

“…The wild-derived inbred strain PWK/Pas controls MCMV infection identically to the C57BL/6J strain with a minor contribution of H-2 genes and despite the lack of Ly49H expression. The Cmv4 locus, mapped to the NKC region on Chromosome 6, might encode a new NK cell activating receptor that enables the detection of MCMV-infected cells as does Ly49H in the C57BL strain [76]. …”