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Cmv4, a New Locus Linked to the NK Cell Gene Complex, Controls Innate Resistance to Cytomegalovirus in Wild-Derived Mice¹

Sonia Girard Adam^*,, Anouk Caraux, Nassima Fodil-Cornu^*,, J. Concepcion Loredo-Osti^*,, Sarah Lesjean-Pottier, Jean Jaubert, Ivan Bubic^¶, Stipan Jonjic^¶, Jean-Louis Guénet, Silvia M. Vidal^2,3,*, and Francesco Colucci^2,4,

^* Department of Human Genetics and McGill Center for Host Resistance, McGill University, Montreal, Canada; Unit of Cytokines and Lymphoid Development, Department of Immunology, Pasteur Institute, Paris, France; Unit of Mammalian Genetics, Department of Developmental Biology, Pasteur Institute, Paris, France; and ^¶ School of Medicine, University of Rijeka, Rijeka, Croatia

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-2D^k. 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.

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				A. H. Davis, N. V. Guseva, B. L. Ball, and J. W. Heusel Characterization of Murine Cytomegalovirus m157 from Infected Cells and Identification of Critical Residues Mediating Recognition by the NK Cell Receptor Ly49H J. Immunol., July 1, 2008; 181(1): 265 - 275. [Abstract] [Full Text] [PDF]