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MCMV glycoprotein gp40 confers virus resistance to CD8+ T cells and NK cells in vivo

Nature Immunology volume 3, pages 529–535 (2002)Cite this article

Abstract

The susceptibility of certain inbred mouse strains to murine cytomegalovirus (MCMV) is related to their inability to generate a strong natural killer (NK) cell response. We addressed here whether the MCMV susceptibility of the BALB/c strain is due to viral functions that control NK cell activation in a strain-specific manner. MCMV expresses two proteins, gp48 and gp40, that are encoded by the genes m06 and m152, respectively; they down-regulate major histocompatibility complex (MHC) class I expression at the plasma membrane. Using MCMV deletion mutants and revertants, we found that gp40 but not gp48 controls NK cell activation. Absence of gp40 improved antiviral NK cell control in BALB/c, but not C57BL/6, mice. Down-regulation of H-60, the high-affinity ligand for the NKG2D receptor, was the mechanism by which gp40 modulates NK cell activation. Thus, a single herpesvirus protein has a dual function in inhibiting both the adaptive as well as the innate immune response.

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Figure 1: Resistance of MCMV to NK cells in BALB/c mice.
Figure 2: Deletion of m152 sensitized the virus to control by NK cells in BALB/c mice.
Figure 3: gp40-mediated control of NK cells is T cell–independent and mouse strain–dependent.
Figure 4: The susceptibility to gp40-mediated control of NK cell activation is determined by ligand on infected cells.
Figure 5: Expression of NKG2D ligand in MCMV-infected MEFs.
Figure 6: gp40 reduced the susceptibility of infected cells to NK cell lysis.
Figure 7: The NK receptors from B6 mice can overcome the m152-gp40–mediated NK inhibition.

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References

  1. Alcami, A. & Koszinowski, U.H. Viral mechanisms of immune evasion. Immunol. Today 21, 447–455 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jonjic, S. et al. Antibodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus. J. Exp. Med. 179, 1713–1717 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Reddehase, M.J. et al. Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs. J. Virol. 55, 264–273 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Polic, B. et al. Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J. Exp. Med. 188, 1047–1054 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tortorella, D., Gewurz, B.E., Furman, M.H., Schust, D.J. & Ploegh, H.L. Viral subversion of the immune system. Annu. Rev. Immunol. 18, 861–926 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Kavanagh, D.G., Gold, M.C., Wagner, M., Koszinowski, U.H. & Hill, A.B. The multiple immune–evasion genes of murine cytomegalovirus are not redundant: m4 and m152 inhibit antigen presentation in a complementary and cooperative fashion. J. Exp. Med. 194, 967–978 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kleijnen, M.F. et al. A mouse cytomegalovirus glycoprotein, gp34, forms a complex with folded class I MHC molecules in the ER which is not retained but is transported to the cell surface. EMBO J. 16, 685–694 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Reusch, U. et al. A cytomegalovirus glycoprotein re-routes MHC class I complexes to lysosomes for degradation. EMBO J. 18, 1081–1091 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ziegler, H. et al. A mouse cytomegalovirus glycoprotein retains MHC class I complexes in the ERGIC/cis-Golgi compartments. Immunity 6, 57–66 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Krmpotic, A. et al. The immunoevasive function encoded by the mouse cytomegalovirus gene m152 protects the virus against T cell control in vivo. J. Exp. Med. 190, 1285–1296 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 

  12. 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  PubMed Central  Google Scholar 

  13. 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 

  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. 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 

  16. 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 

  17. Lee, S.H. et al. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nature Genet. 28, 42–45 (2001).

    CAS  PubMed  Google Scholar 

  18. Daniels, K.A. et al. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J. Exp. Med. 194, 29–44 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Brown, M.G. et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Diefenbach, A. & Raulet, D.H. Strategies for target cell recognition by natural killer cells. Immunol. Rev. 181, 170–184 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Biassoni, R. et al. Human natural killer cell receptors and co-receptors. Immunol. Rev. 181, 203–214 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Cosman, D. et al. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14, 123–133 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Bauer, S. et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727–729 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Wolan, D.W. et al. Crystal structure of the murine NK cell-activating receptor NKG2D at 1.95 A. Nature Immunol. 2, 248–254 (2001).

    Article  CAS  Google Scholar 

  25. Diefenbach, A., Jamieson, A.M., Liu, S.D., Shastri, N. & Raulet, D.H. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nature Immunol. 1, 119–126 (2000).

    Article  CAS  Google Scholar 

  26. Groh, V. et al. Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nature Immunol. 2, 255–260 (2001).

    Article  CAS  Google Scholar 

  27. Cerwenka, A. et al. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 12, 721–727 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Malarkannan, S. et al. The molecular and functional characterization of a dominant minor H antigen, H60. J. Immunol. 161, 3501–3509 (1998).

    CAS  PubMed  Google Scholar 

  29. Peng, Y., Falck-Pedersen, E. & Elkon, K.B. Variation in adenovirus transgene expression between BALB/c and C57BL/6 mice is associated with differences in interleukin-12 and γ interferon production and NK cell activation. J. Virol. 75, 4540–4550 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Del Val, M., Schlicht, H.J., Ruppert, T., Reddehase, M.J. & Koszinowski, U.H. Efficient processing of an antigenic sequence for presentation by MHC class I molecules depends on its neighboring residues in the protein. Cell 66, 1145–1153 (1991).

    Article  CAS  PubMed  Google Scholar 

  31. Scalzo, A.A., Lyons, P.A., Fitzgerald, N.A., Forbes, C.A. & Shellam, G.R. The BALB.B6-Cmv1r mouse: a strain congenic for Cmv1 and the NK gene complex. Immunogenetics 41, 148–151 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Scalzo, A.A. et al. Development of intra-natural killer complex (NKC) recombinant and congenic mouse strains for mapping and functional analysis of NK cell regulatory loci. Immunogenetics 49, 238–241 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Del Val, M. et al. Cytomegalovirus prevents antigen presentation by blocking the transport of peptide-loaded major histocompatibility complex class I molecules into the medial-Golgi compartment. J. Exp. Med. 176, 729–738 (1992).

    Article  CAS  PubMed  Google Scholar 

  34. Ziegler, H., Muranyi, W., Burgert, H.G., Kremmer, E. & Koszinowski, U.H. The luminal part of the murine cytomegalovirus glycoprotein gp40 catalyzes the retention of MHC class I molecules. EMBO J. 19, 870–881 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gutermann, A. et al. Strategies for the identification analysis of viral immune evasion genes: Cytomegalovirus as example. Curr. Top. Microbiol. (in the press, 2002).

  36. Karre, K., Ljunggren, H.G., Piontek, G. & Kiessling, R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319, 675–678 (1986).

    Article  CAS  PubMed  Google Scholar 

  37. Wu, J. et al. An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285, 730–732 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Diefenbach, A., Jensen, E.R., Jamieson, A.M. & Raulet, D.H. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413, 165–171 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cerwenka, A., Baron, J.L. & Lanier, L.L. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc. Natl. Acad. Sci. USA 98, 11521–11526 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Girardi, M. et al. Regulation of Cutaneous Malignancy by γδ T Cells. Science 294, 605–609 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. 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 (2002); advance online publication, April 11 2002 (10.1126/science.1070884).

  42. Sutherland, C.L., Chalupny, N.J. & Cosman, D. The UL16-binding proteins, a novel family of MHC class I-related ligands for NKG2D, activate natural killer cell functions. Immunol. Rev. 181, 185–192 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Farrell, H.E. et al. Inhibition of natural killer cells by a cytomegalovirus MHC class I homologue in vivo. Nature 386, 510–514 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Reyburn, H.T. et al. The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 386, 514–517 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Tomasec, P. et al. Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287, 1031 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Ulbrecht, M. et al. Cutting edge: the human cytomegalovirus UL40 gene product contains a ligand for HLA-E and prevents NK cell-mediated lysis. J. Immunol. 164, 5019–5022 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Crnkovic-Mertens, I. et al. Virus attenuation after deletion of the cytomegalovirus Fc receptor gene is not due to antibody control. J. Virol. 72, 1377–1382 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Cobbold, S.P., Jayasuriya, A., Nash, A., Prospero, T.D. & Waldmann, H. Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature 312, 548–551 (1984).

    Article  CAS  PubMed  Google Scholar 

  49. Koo, G.C. & Peppard, J.R. Establishment of monoclonal anti-Nk-1. 1 antibody. Hybridoma 3, 301–303 (1984).

    Article  CAS  PubMed  Google Scholar 

  50. Schatz, P.J. Use of peptide libraries to map the substrate specificity of a peptide-modifying enzyme: a 13 residue consensus peptide specifies biotinylation in Escherichia coli. Biotechnology 11, 1138–1143 (1993).

    CAS  PubMed  Google Scholar 

  51. Busch, D.H., Pilip, I.M., Vijh, S. & Pamer, E.G. Coordinate regulation of complex T cell populations responding to bacterial infection. Immunity 8, 353–362 (1998).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Supported by the Croatian Ministry of Science (grant number 006204 to S. J.) and Deutsche Forschungsgemeinschaft (grant number SFB 455 to U. H. K.) and BMBF (grant number 0312200A to H. H.). We thank L. Lanier and E. Mocarski for advice during the study and J. Trgovcich and B. Polic for critical comments during the manuscript preparation.

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Authors and Affiliations

  1. Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia

    Astrid Krmpotić, Ivan Bubić, Milena Hasan & Stipan Jonjić

  2. Institute of Microbiology, Immunology and Hygiene, Technical University, Munich, Germany

    Dirk H. Busch & Friedemann Gebhardt

  3. Robert Koch-Institute, Berlin, Germany

    Hartmut Hengel

  4. Department of Microbiology, University of Western Australia, Nedlands, WA, Australia

    Anthony A. Scalzo

  5. Max von Pettenkofer Institute, Munich, Germany

    Ulrich H. Koszinowski

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Correspondence to Stipan Jonjić.

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Krmpotić, A., Busch, D., Bubić, I. et al. MCMV glycoprotein gp40 confers virus resistance to CD8+ T cells and NK cells in vivo. Nat Immunol 3, 529–535 (2002). https://doi.org/10.1038/ni799

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