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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

Nature Genetics volume 37, pages 593–599 (2005)Cite this article

Abstract

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 (H2k) and MCMV-susceptible BALB/c (H2d) and BALB.K (H2k) 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 H2k 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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Figure 1: Haplotype mapping on chromosome 6 in the vicinity of Cmv1.
Figure 2: Genetic analysis of MCMV resistance in MA/My mice.
Figure 3: Activation of Ly49P reporter cells by MCMV-infected cells.
Figure 4: Ly49P recognition of MCMV-infected cells is target MHC-dependent.
Figure 5: Characterization of Ly49P interaction with an infected cell.

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Acknowledgements

We thank S.-H. Lee for the initial characterization of the MA/My strain; F. Takei for providing the YE1/48 antibody for depletion experiments; D. Albert and M.-H. Lacombe for technical support; M. Reuben for editorial assistance; and P. Gros, E. Schurr and M. Fujiwara for critical reading of the manuscript. This work was supported by grants from the Canadian Institutes of Health Research and the Canadian Genetic Diseases Network (Network of Centres of Excellence program). A.K., S.G.A. and J.-C.L.-O. were Canadian Institutes of Health Research Training Fellows in Infectious Diseases and Autoimmunity. A.K. was also supported by a McGill Majors Fellowship. M.B.L., T.P. and L.L.L. are supported by a grant from the US National Institutes of Health. L.L.L. is an American Cancer Society Research Professor. S.M.V. is a Canada Research Chair.

Author information

Author notes

  1. Marie-Pierre Desrosiers and Agnieszka Kielczewska: These authors contributed equally to this work.

Authors and Affiliations

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

    Marie-Pierre Desrosiers, Agnieszka Kielczewska, J-C Loredo-Osti, Sonia Girard Adam, Kenneth Morgan & Silvia M Vidal

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

    Marie-Pierre Desrosiers, Agnieszka Kielczewska, Sonia Girard Adam, Kenneth Morgan & Silvia M Vidal

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

    Andrew P Makrigiannis

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

    Suzanne Lemieux

  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, 94143-0414, California, USA

    Trung Pham, Melissa B Lodoen & Lewis L Lanier

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

    Kenneth Morgan

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

    Silvia M Vidal

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Correspondence to Silvia M Vidal.

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Supplementary information

Supplementary Fig. 1

Expression of the Ly49P receptor on MA/My NK cells, and the effect of depletion of Ly49P+ NK cells on MCMV resistance. (PDF 68 kb)

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Desrosiers, MP., Kielczewska, A., Loredo-Osti, JC. et al. 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. Nat Genet 37, 593–599 (2005). https://doi.org/10.1038/ng1564

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