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Article
Nature Genetics  37, 593 - 599 (2005)
Published online: 15 May 2005; | doi:10.1038/ng1564

Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell−mediated innate resistance to cytomegalovirus infection

Marie-Pierre Desrosiers1, 2, 8, Agnieszka Kielczewska1, 2, 8, J-C Loredo-Osti1, Sonia Girard Adam1, 2, Andrew P Makrigiannis3, Suzanne Lemieux4, Trung Pham5, Melissa B Lodoen5, Kenneth Morgan1, 2, 6, Lewis L Lanier5 & Silvia M Vidal1, 2, 7

1  Department of Human Genetics, McGill University, Montreal, Quebec, H3A 1B1, Canada.

2  McGill Centre for the Study of Host Resistance, McGill University, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada.

3  Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Quebec, H2W 1R7, Canada.

4  INRS-Université du Québec, Laval, Quebec, H7V 1B7, Canada.

5  Department of Microbiology and Immunology, the Biomedical Sciences Graduate Program and the Cancer Research Institute, University of California San Francisco, 513 Parnassus Avenue, Box 0414, San Francisco, California 94143-0414, USA.

6  Department of Medicine, McGill University, Montreal, Quebec, Canada.

7  Department of Microbiology and Immunology, McGill University, Montreal, Quebec, H3A 2B4, Canada.

8  These authors contributed equally to this work.

Correspondence should be addressed to Silvia M Vidal silvia.vidal@mcgill.ca
Experimental infection with mouse cytomegalovirus (MCMV) has been used to elucidate the intricate host-pathogen mechanisms that determine innate resistance to infection. Linkage analyses in F2 progeny from MCMV-resistant MA/My (H2 k) and MCMV-susceptible BALB/c (H2 d) and BALB.K (H2 k) mouse strains indicated that only the combination of alleles encoded by a gene in the Klra (also called Ly49) cluster on chromosome 6, and one in the major histocompatibility complex (H2) on chromosome 17, is associated with virus resistance. We found that natural killer cell−activating receptor Ly49P specifically recognized MCMV-infected cells, dependent on the presence of the H2 k haplotype. This binding was blocked using antibodies to H-2Dk but not antibodies to H-2Kk. These results are suggestive of a new natural killer cell mechanism implicated in MCMV resistance, which depends on the functional interaction of the Ly49P receptor and the major histocompatibility complex class I molecule H-2Dk on MCMV-infected cells.

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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