Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Britt, W.J. & Alford, C.A. Cytomegalovirus. in Fields Virology (eds. Fields, B.N., Knipe, D.M. & Howley, P.M.) 2493–2524 (Lippincott-Raven, Philadelphia, 1996).

    Google Scholar 

  2. Reusser, P. Management of viral infections in immunocompromised cancer patients. Swiss. Med. Wkly. 132, 374–378 (2002).

    PubMed  Google Scholar 

  3. Soderberg-Naucler, C. & Emery, V.C. Viral infections and their impact on chronic renal allograft dysfunction. Transplantation 71, SS24–SS30 (2001).

    CAS  PubMed  Google Scholar 

  4. Trincado, D.E. & Rawlinson, W.D. Congenital and perinatal infections with cytomegalovirus. J. Paediatr. Child Health 37, 187–192 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Biron, C.A., Byron, K.S. & Sullivan, J.L. Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320, 1731–1735 (1989).

    Article  CAS  PubMed  Google Scholar 

  6. Biron, C.A., Nguyen, K.B., Pien, G.C., Cousens, L.P. & Salazar-Mather, T.P. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Chalmer, J.E., Mackenzie, J.S. & Stanley, N.F. Resistance to murine cytomegalovirus linked to the major histocompatibility complex of the mouse. J. Gen. Virol. 37, 107–114 (1977).

    Article  CAS  PubMed  Google Scholar 

  8. Grundy, J.E., Mackenzie, J.S. & Stanley, N.F. Influence of H-2 and non-H-2 genes on resistance to murine cytomegalovirus infection. Infect. Immun. 32, 277–286 (1981).

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Scalzo, A.A., Fitzgerald, N.A., Simmons, A., La Vista, A.B. & Shellam, G.R. Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J. Exp. Med. 171, 1469–1483 (1990).

    Article  CAS  PubMed  Google Scholar 

  10. Scalzo, A.A. et al. The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells. J. Immunol. 149, 581–589 (1992).

    CAS  PubMed  Google Scholar 

  11. Depatie, C., Muise, E., Lepage, P., Gros, P. & Vidal, S.M. High-resolution linkage map in the proximity of the host resistance locus Cmv1. Genomics 39, 154–163 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Scalzo, A.A. et al. Genetic mapping of Cmv1 in the region of mouse chromosome 6 encoding the NK gene complex-associated loci Ly49 and musNKR-P1. Genomics 27, 435–441 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Brown, M.G. et al. A 2-Mb YAC contig and physical map of the natural killer gene complex on mouse chromosome 6. Genomics 42, 16–25 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Brown, M.G., Scalzo, A.A., Matsumoto, K. & Yokoyama, W.M. The natural killer gene complex: a genetic basis for understanding natural killer cell function and innate immunity. Immunol. Rev. 155, 53–65 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Yokoyama, W.M. & Plougastel, B.F. Immune functions encoded by the natural killer gene complex. Nat. Rev. Immunol. 3, 304–316 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Long, E.O. Regulation of immune responses through inhibitory receptors. Annu. Rev. Immunol. 17, 875–904 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Arase, H., Mocarski, E.S., Campbell, A.E., Hill, A.B. & Lanier, L.L. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Smith, H.R. et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl. Acad. Sci. USA 99, 8826–8831 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lee, S.H. et al. Haplotype mapping indicates two independent origins for the Cmv1s susceptibility allele to cytomegalovirus infection and refines its localization within the Ly49 cluster. Immunogenetics 53, 501–505 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Makrigiannis, A.P. et al. A BAC contig map of the Ly49 gene cluster in 129 mice reveals extensive differences in gene content relative to C57BL/6 mice. Genomics 79, 437–444 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Arase, H. & Lanier, L.L. Specific recognition of virus-infected cells by paired NK receptors. Rev. Med. Virol. 14, 83–93 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Makrigiannis, A.P. et al. Class I MHC-binding characteristics of the 129/J Ly49 repertoire. J. Immunol. 166, 5034–5043 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Silver, E.T. et al. Ly-49P activates NK-mediated lysis by recognizing H-2Dd. J. Immunol. 165, 1771–1781 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Makrigiannis, A.P. et al. Cloning and characterization of a novel activating Ly49 closely related to Ly49A. J. Immunol. 163, 4931–4938 (1999).

    CAS  PubMed  Google Scholar 

  25. Nakamura, M.C., Hayashi, S., Niemi, E.C., Ryan, J.C. & Seaman, W.E. Activating Ly-49D and inhibitory Ly-49A natural killer cell receptors demonstrate distinct requirements for interaction with H2-D(d). J. Exp. Med. 192, 447–454 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nakamura, M.C. & Seaman, W.E. Ligand interactions by activating and inhibitory Ly-49 receptors. Immunol. Rev. 181, 138–148 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Peruzzi, M., Wagtmann, N. & Long, E.O. A p70 killer cell inhibitory receptor specific for several HLA-B allotypes discriminates among peptides bound to HLA-B*2705. J. Exp. Med. 184, 1585–1590 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Franksson, L. et al. Peptide dependency and selectivity of the NK cell inhibitory receptor Ly-49C. Eur. J. Immunol. 29, 2748–2758 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Radaev, S. & Sun, P.D. Structure and function of natural killer cell surface receptors. Annu. Rev. Biophys. Biomol. Struct. 32, 93–114 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Dam, J. et al. Variable MHC class I engagement by Ly49 natural killer cell receptors demonstrated by the crystal structure of Ly49C bound to H-2K(b). Nat. Immunol. 4, 1213–1222 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Trowsdale, J. et al. The genomic context of natural killer receptor extended gene families. Immunol. Rev. 181, 20–38 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Belkin, D. et al. Killer cell Ig-like receptor and leukocyte Ig-like receptor transgenic mice exhibit tissue- and cell-specific transgene expression. J. Immunol. 171, 3056–3063 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Khakoo, S.I. et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305, 872–874 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Martin, M.P. et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat. Genet. 31, 429–434 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Scalzo, A.A., Farrell, H. & Karupiah, G. Techniques for studying murine natural killer cells in defense against viral infection. in Natural Killer Cell Protocols, Cellular and Molecular Methods (eds. Campbell, K.S. & Colonna, M.) 163–177 (Humana, Totowa, New Jersey, 2000).

    Chapter  Google Scholar 

  36. Truett, G.E. et al. Preparation of PCR-quality mouse genomic DNA with hot sodium hydroxide and tris (HotSHOT). Biotechniques 29, 52, 54 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Depatie, C. et al. Assessment of Cmv1 candidates by genetic mapping and in vivo antibody depletion of NK cell subsets. Int. Immunol. 11, 1541–1551 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Depatie, C. et al. Sequence-ready BAC contig, physical, and transcriptional map of a 2-Mb region overlapping the mouse chromosome 6 host-resistance locus Cmv1. Genomics 66, 161–174 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Peng, S.L. & Craft, J. PCR-RFLP genotyping of murine MHC haplotypes. Biotechniques 21, 362–368 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Silver, E.T., Gong, D., Hazes, B. & Kane, K.P. Ly-49W, an activating receptor of nonobese diabetic mice with close homology to the inhibitory receptor Ly-49G, recognizes H-2D(k) and H-2D(d). J. Immunol. 166, 2333–2341 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Manly, K.F. & Olson, J.M. Overview of QTL mapping software and introduction to map manager QT. Mamm. Genome 10, 327–334 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Pierce, C.A., Block, R.A. & Aquinis, H. Cautionary note on reporting eta-squared from multifactor ANOVA designs. Educ. Psychol. Meas. 64, 916–924 (2004).

    Article  Google Scholar 

Download references

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

Authors
  1. Marie-Pierre Desrosiers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Agnieszka Kielczewska
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J-C Loredo-Osti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sonia Girard Adam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew P Makrigiannis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Suzanne Lemieux
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Trung Pham
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Melissa B Lodoen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kenneth Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lewis L Lanier
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Silvia M Vidal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Silvia M Vidal.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1564

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing