Skip to main content

Advertisement

SpringerLink
Log in

Innate immunity regulates adaptive immune response: lessons learned from studying the interplay between NK and CD8+ T cells during MCMV infection

  • Review
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Natural killer (NK) cells play a crucial role in early immune response against cytomegalovirus infection. A large and mounting body of data indicate that these cells are involved in the regulation of the adaptive immune response as well. By using mouse cytomegalovirus (MCMV) as a model, several groups provided novel insights into the role of NK cells in the development and kinetics of antiviral CD8+ T cell response. Depending on infection conditions, virus strain and the genetic background of mice used, NK cells are either positive or negative regulators of the CD8+ T cell response. At present, there is no unique explanation for the observed differences between various experimental systems used. In this review we discuss the mechanisms involved in the interplay between NK and CD8+ T cells in the early control of MCMV infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Krmpotic A, Bubic I, Polic B, Lucin P, Jonjic S (2003) Pathogenesis of murine cytomegalovirus infection. Microbes Infect 5(13):1263–1277

    Article  PubMed  CAS  Google Scholar 

  2. Reddehase MJ, Simon CO, Seckert CK, Lemmermann N, Grzimek NK (2008) Murine model of cytomegalovirus latency and reactivation. Curr Top Microbiol Immunol 325:315–331

    Article  PubMed  CAS  Google Scholar 

  3. Reddehase MJ (2002) Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat Rev Immunol 2(11):831–844. doi:10.1038/nri932

    Article  PubMed  CAS  Google Scholar 

  4. Jonjic S, Bubic I, Krmpotic A (2006) Innate immunity to cytomegaloviruses. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Wymondham, pp 285–319

    Google Scholar 

  5. Takeda K, Akira S (2007) Toll-like receptors. Curr Protoc Immunol 14:12. doi:10.1002/0471142735.im1412s77

    PubMed  Google Scholar 

  6. Krug A, French AR, Barchet W, Fischer JA, Dzionek A, Pingel JT, Orihuela MM, Akira S, Yokoyama WM, Colonna M (2004) TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 21(1):107–119. doi:10.1016/j.immuni.2004.06.007

    Article  PubMed  CAS  Google Scholar 

  7. Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, Mudd S, Shamel L, Sovath S, Goode J, Alexopoulou L, Flavell RA, Beutler B (2004) Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Nat Acad Sci USA 101(10):3516–3521. doi:10.1073/pnas.0400525101

    Article  PubMed  CAS  Google Scholar 

  8. Vidal SM, Lanier LL (2006) NK cell recognition of mouse cytomegalovirus-infected cells. Curr Top Microbiol Immunol 298:183–206

    Article  PubMed  CAS  Google Scholar 

  9. Scalzo AA (2002) Successful control of viruses by NK cells–a balance of opposing forces? Trends Microbiol 10(10):470–474

    Article  PubMed  CAS  Google Scholar 

  10. Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL (2002) Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296(5571):1323–1326. doi:10.1126/science.1070884

    Article  PubMed  CAS  Google Scholar 

  11. Smith HR, Heusel JW, Mehta IK, Kim S, Dorner BG, Naidenko OV, Iizuka K, Furukawa H, Beckman DL, Pingel JT, Scalzo AA, Fremont DH, Yokoyama WM (2002) Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc Nat Acad Sci USA 99(13):8826–8831. doi:10.1073/pnas.092258599

    PubMed  CAS  Google Scholar 

  12. Bubic I, Wagner M, Krmpotic A, Saulig T, Kim S, Yokoyama WM, Jonjic S, Koszinowski UH (2004) Gain of virulence caused by loss of a gene in murine cytomegalovirus. J Virol 78(14):7536–7544. doi:10.1128/JVI.78.14.7536-7544.2004

    Article  PubMed  CAS  Google Scholar 

  13. Fodil-Cornu N, Lee SH, Belanger S, Makrigiannis AP, Biron CA, Buller RM, Vidal SM (2008) Ly49 h-deficient C57BL/6 mice: a new mouse cytomegalovirus-susceptible model remains resistant to unrelated pathogens controlled by the NK gene complex. J Immunol 181(9):6394–6405

    PubMed  CAS  Google Scholar 

  14. Scalzo AA, Fitzgerald NA, Simmons A, La Vista AB, Shellam GR (1990) Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J Exp Med 171(5):1469–1483

    Article  PubMed  CAS  Google Scholar 

  15. Babic M, Krmpotic A, Jonjic S (2011) All is fair in virus-host interactions: NK cells and cytomegalovirus. Trends Mol Med 17(11):677–685. doi:10.1016/j.molmed.2011.07.003

    Article  PubMed  CAS  Google Scholar 

  16. Lisnic VJ, Krmpotic A, Jonjic S (2010) Modulation of natural killer cell activity by viruses. Curr Opin Microbiol 13(4):530–539. doi:10.1016/j.mib.2010.05.011

    Article  PubMed  CAS  Google Scholar 

  17. Lenac T, Arapovic J, Traven L, Krmpotic A, Jonjic S (2008) Murine cytomegalovirus regulation of NKG2D ligands. Med Microbiol Immunol 197(2):159–166. doi:10.1007/s00430-008-0080-7

    Article  PubMed  Google Scholar 

  18. Biron CA (2012) Yet another role for natural killer cells: cytotoxicity in immune regulation and viral persistence. Proc Nat Acad Sci USA 109(6):1814–1815. doi:10.1073/pnas.1120528109

    Article  PubMed  CAS  Google Scholar 

  19. Raulet DH (2004) Interplay of natural killer cells and their receptors with the adaptive immune response. Nat Immunol 5(10):996–1002. doi:10.1038/ni1114

    Article  PubMed  CAS  Google Scholar 

  20. Dalod M, Salazar-Mather TP, Malmgaard L, Lewis C, Asselin-Paturel C, Briere F, Trinchieri G, Biron CA (2002) Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J Exp Med 195(4):517–528

    Article  PubMed  CAS  Google Scholar 

  21. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220. doi:10.1146/annurev.immunol.17.1.189

    Article  PubMed  CAS  Google Scholar 

  22. Delale T, Paquin A, Asselin-Paturel C, Dalod M, Brizard G, Bates EE, Kastner P, Chan S, Akira S, Vicari A, Biron CA, Trinchieri G, Briere F (2005) MyD88-dependent and -independent murine cytomegalovirus sensing for IFN-alpha release and initiation of immune responses in vivo. J Immunol 175(10):6723–6732

    PubMed  CAS  Google Scholar 

  23. Andrews DM, Andoniou CE, Scalzo AA, van Dommelen SL, Wallace ME, Smyth MJ, Degli-Esposti MA (2005) Cross-talk between dendritic cells and natural killer cells in viral infection. Mol Immunol 42(4):547–555. doi:10.1016/j.molimm.2004.07.040

    Article  PubMed  CAS  Google Scholar 

  24. Bevan MJ (2006) Cross-priming. Nat Immunol 7(4):363–365. doi:10.1038/ni0406-363

    Article  PubMed  CAS  Google Scholar 

  25. Andoniou CE, van Dommelen SL, Voigt V, Andrews DM, Brizard G, Asselin-Paturel C, Delale T, Stacey KJ, Trinchieri G, Degli-Esposti MA (2005) Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity. Nat Immunol 6(10):1011–1019. doi:10.1038/ni1244

    Article  PubMed  CAS  Google Scholar 

  26. Andrews DM, Scalzo AA, Yokoyama WM, Smyth MJ, Degli-Esposti MA (2003) Functional interactions between dendritic cells and NK cells during viral infection. Nat Immunol 4(2):175–181. doi:10.1038/ni880

    Article  PubMed  CAS  Google Scholar 

  27. Su HC, Nguyen KB, Salazar-Mather TP, Ruzek MC, Dalod MY, Biron CA (2001) NK cell functions restrain T cell responses during viral infections. Eur J Immunol 31(10):3048–3055. doi:10.1002/1521-4141(2001010)31:10<3048:AID-IMMU3048>3.0.CO;2-1

    Article  PubMed  CAS  Google Scholar 

  28. Robbins SH, Bessou G, Cornillon A, Zucchini N, Rupp B, Ruzsics Z, Sacher T, Tomasello E, Vivier E, Koszinowski UH, Dalod M (2007) Natural killer cells promote early CD8 T cell responses against cytomegalovirus. PLoS Pathog 3(8):e123. doi:10.1371/journal.ppat.0030123

    Article  PubMed  Google Scholar 

  29. Lee SH, Kim KS, Fodil-Cornu N, Vidal SM, Biron CA (2009) Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection. J Exp Med 206(10):2235–2251. doi:10.1084/jem.20082387

    Article  PubMed  CAS  Google Scholar 

  30. Andrews DM, Estcourt MJ, Andoniou CE, Wikstrom ME, Khong A, Voigt V, Fleming P, Tabarias H, Hill GR, van der Most RG, Scalzo AA, Smyth MJ, Degli-Esposti MA (2010) Innate immunity defines the capacity of antiviral T cells to limit persistent infection. J Exp Med 207(6):1333–1343. doi:10.1084/jem.20091193

    Article  PubMed  CAS  Google Scholar 

  31. Slavuljica I, Busche A, Babic M, Mitrovic M, Gasparovic I, Cekinovic D, Markova Car E, Pernjak Pugel E, Cikovic A, Lisnic VJ, Britt WJ, Koszinowski U, Messerle M, Krmpotic A, Jonjic S (2010) Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties. J Clin Invest 120(12):4532–4545. doi:10.1172/JCI43961

    Article  PubMed  CAS  Google Scholar 

  32. Stadnisky MD, Xie X, Coats ER, Bullock TN, Brown MG (2011) Self MHC class I-licensed NK cells enhance adaptive CD8 T-cell viral immunity. Blood 117(19):5133–5141. doi:10.1182/blood-2010-12-324632

    Article  PubMed  CAS  Google Scholar 

  33. Mitrovic M, Arapovic J, Jordan S, Fodil-Cornu N, Ebert S, Vidal SM, Krmpotic A, Reddehase MJ, Jonjic S (2012) The NK cell response to mouse cytomegalovirus infection affects the level and kinetics of the early CD8(+) T-cell response. J Virol 86(4):2165–2175. doi:10.1128/JVI.06042-11

    Article  PubMed  CAS  Google Scholar 

  34. Waggoner SN, Cornberg M, Selin LK, Welsh RM (2012) Natural killer cells act as rheostats modulating antiviral T cells. Nature 481(7381):394–398. doi:10.1038/nature10624

    CAS  Google Scholar 

  35. Lang PA, Lang KS, Xu HC, Grusdat M, Parish IA, Recher M, Elford AR, Dhanji S, Shaabani N, Tran CW, Dissanayake D, Rahbar R, Ghazarian M, Brustle A, Fine J, Chen P, Weaver CT, Klose C, Diefenbach A, Haussinger D, Carlyle JR, Kaech SM, Mak TW, Ohashi PS (2012) Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proc Nat Acad Sci USA 109(4):1210–1215. doi:10.1073/pnas.1118834109

    Article  PubMed  CAS  Google Scholar 

  36. Cerwenka A, Bakker AB, McClanahan T, Wagner J, Wu J, Phillips JH, Lanier LL (2000) Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 12(6):721–727

    Article  PubMed  CAS  Google Scholar 

  37. Daniels KA, Devora G, Lai WC, O’Donnell CL, Bennett M, Welsh RM (2001) Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J Exp Med 194(1):29–44

    Article  PubMed  CAS  Google Scholar 

  38. Kielczewska A, Pyzik M, Sun T, Krmpotic A, Lodoen MB, Munks MW, Babic M, Hill AB, Koszinowski UH, Jonjic S, Lanier LL, Vidal SM (2009) Ly49P recognition of cytomegalovirus-infected cells expressing H2-Dk and CMV-encoded m04 correlates with the NK cell antiviral response. J Exp Med 206(3):515–523. doi:10.1084/jem.20080954

    Article  PubMed  CAS  Google Scholar 

  39. Babic M, Pyzik M, Zafirova B, Mitrovic M, Butorac V, Lanier LL, Krmpotic A, Vidal SM, Jonjic S (2010) Cytomegalovirus immunoevasin reveals the physiological role of “missing self” recognition in natural killer cell dependent virus control in vivo. J Exp Med 207(12):2663–2673. doi:10.1084/jem.20100921

    Article  PubMed  CAS  Google Scholar 

  40. Kleijnen MF, Huppa JB, Lucin P, Mukherjee S, Farrell H, Campbell AE, Koszinowski UH, Hill AB, Ploegh HL (1997) 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(4):685–694. doi:10.1093/emboj/16.4.685

    Article  PubMed  CAS  Google Scholar 

  41. Tay CH, Welsh RM (1997) Distinct organ-dependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells. J Virol 71(1):267–275

    PubMed  CAS  Google Scholar 

  42. Loh J, Chu DT, O’Guin AK, Yokoyama WM, Virgin HWt (2005) Natural killer cells utilize both perforin and gamma interferon to regulate murine cytomegalovirus infection in the spleen and liver. J Virol 79(1):661–667. doi:10.1128/JVI.79.1.661-667.2005

    Article  PubMed  CAS  Google Scholar 

  43. Jonjic S, Pavic I, Lucin P, Rukavina D, Koszinowski UH (1990) Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes. J Virol 64(11):5457–5464

    PubMed  CAS  Google Scholar 

  44. Jonjic S, Mutter W, Weiland F, Reddehase MJ, Koszinowski UH (1989) Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes. J Exp Med 169(4):1199–1212

    Article  PubMed  CAS  Google Scholar 

  45. Campbell AE, Cavanaugh VJ, Slater JS (2008) The salivary glands as a privileged site of cytomegalovirus immune evasion and persistence. Med Microbiol Immunol 197(2):205–213. doi:10.1007/s00430-008-0077-2

    Article  PubMed  Google Scholar 

  46. Walton SM, Mandaric S, Torti N, Zimmermann A, Hengel H, Oxenius A (2011) Absence of cross-presenting cells in the salivary gland and viral immune evasion confine cytomegalovirus immune control to effector CD4 T cells. PLoS Pathog 7(8):e1002214. doi:10.1371/journal.ppat.1002214

    Article  PubMed  CAS  Google Scholar 

  47. Polic B, Hengel H, Krmpotic A, Trgovcich J, Pavic I, Luccaronin P, Jonjic S, Koszinowski UH (1998) Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med 188(6):1047–1054

    Article  PubMed  CAS  Google Scholar 

  48. Pinto AK, Hill AB (2005) Viral interference with antigen presentation to CD8+ T cells: lessons from cytomegalovirus. Viral Immunol 18(3):434–444. doi:10.1089/vim.2005.18.434

    Article  PubMed  CAS  Google Scholar 

  49. Doom CM, Hill AB (2008) MHC class I immune evasion in MCMV infection. Med Microbiol Immunol 197(2):191–204. doi:10.1007/s00430-008-0089-y

    Article  PubMed  CAS  Google Scholar 

  50. Orange JS (2008) Formation and function of the lytic NK-cell immunological synapse. Nat Rev Immunol 8(9):713–725. doi:10.1038/nri2381

    Article  PubMed  CAS  Google Scholar 

  51. Guidotti LG, Chisari FV (2001) Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 19:65–91. doi:10.1146/annurev.immunol.19.1.65

    Article  PubMed  CAS  Google Scholar 

  52. Voskoboinik I, Smyth MJ, Trapani JA (2006) Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 6(12):940–952. doi:10.1038/nri1983

    Article  PubMed  CAS  Google Scholar 

  53. Hehlgans T, Pfeffer K (2005) The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology 115(1):1–20. doi:10.1111/j.1365-2567.2005.02143.x

    Article  PubMed  CAS  Google Scholar 

  54. Strasser A, O’Connor L, Dixit VM (2000) Apoptosis signaling. Annu Rev Biochem 69:217–245. doi:10.1146/annurev.biochem.69.1.217

    Article  PubMed  CAS  Google Scholar 

  55. Baillie J, Sahlender DA, Sinclair JH (2003) Human cytomegalovirus infection inhibits tumor necrosis factor alpha (TNF-alpha) signaling by targeting the 55-kilodalton TNF-alpha receptor. J Virol 77(12):7007–7016

    Article  PubMed  CAS  Google Scholar 

  56. Popkin DL, Virgin HWt (2003) Murine cytomegalovirus infection inhibits tumor necrosis factor alpha responses in primary macrophages. J Virol 77(18):10125–10130

    Article  PubMed  CAS  Google Scholar 

  57. Pavic I, Polic B, Crnkovic I, Lucin P, Jonjic S, Koszinowski UH (1993) Participation of endogenous tumour necrosis factor alpha in host resistance to cytomegalovirus infection. J Gen Virol 74(Pt 10):2215–2223

    Article  PubMed  CAS  Google Scholar 

  58. Muller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, Aguet M (1994) Functional role of type I and type II interferons in antiviral defense. Science 264(5167):1918–1921

    Article  PubMed  CAS  Google Scholar 

  59. Orange JS, Biron CA (1996) Characterization of early IL-12, IFN-alphabeta, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection. J Immunol 156(12):4746–4756

    PubMed  CAS  Google Scholar 

  60. Dunn GP, Bruce AT, Sheehan KC, Shankaran V, Uppaluri R, Bui JD, Diamond MS, Koebel CM, Arthur C, White JM, Schreiber RD (2005) A critical function for type I interferons in cancer immunoediting. Nat Immunol 6(7):722–729. doi:10.1038/ni1213

    Article  PubMed  CAS  Google Scholar 

  61. Nguyen KB, Salazar-Mather TP, Dalod MY, Van Deusen JB, Wei XQ, Liew FY, Caligiuri MA, Durbin JE, Biron CA (2002) Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol 169(8):4279–4287

    PubMed  CAS  Google Scholar 

  62. Geurs TL, Zhao YM, Hill EB, French AR (2009) Ly49H engagement compensates for the absence of type I interferon signaling in stimulating NK cell proliferation during murine cytomegalovirus infection. J Immunol 183(9):5830–5836. doi:10.4049/jimmunol.0901520

    Article  PubMed  CAS  Google Scholar 

  63. Huber JP, Farrar JD (2011) Regulation of effector and memory T-cell functions by type I interferon. Immunology 132(4):466–474. doi:10.1111/j.1365-2567.2011.03412.x

    Article  PubMed  CAS  Google Scholar 

  64. Montoya M, Schiavoni G, Mattei F, Gresser I, Belardelli F, Borrow P, Tough DF (2002) Type I interferons produced by dendritic cells promote their phenotypic and functional activation. Blood 99(9):3263–3271

    Article  PubMed  CAS  Google Scholar 

  65. Welsh RM, Bahl K, Marshall HD, Urban SL (2012) Type 1 interferons and antiviral CD8 T-cell responses. PLoS Pathog 8(1):e1002352. doi:10.1371/journal.ppat.1002352

    Article  PubMed  CAS  Google Scholar 

  66. Curtsinger JM, Valenzuela JO, Agarwal P, Lins D, Mescher MF (2005) Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol 174(8):4465–4469

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by NIH grants 1R01AI083201-01, and by the Impuls- und Vernetzungsfonds of the Helmholtz Association (grant “Viral strategies of immune evasion”; VH-VI-424-4) to S. Jonjic. J. Arapovic is supported by the Federal Ministry of Education and Science, Bosnia and Herzegovina (grant “Prevalence of congenital CMV infection in Herzegovina”).

Author information

Authors and Affiliations

  1. Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, B. Branchetta 20, 51 000, Rijeka, Croatia

    Maja Mitrović, Jurica Arapović, Astrid Krmpotić & Stipan Jonjić

  2. Faculty of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina

    Jurica Arapović

  3. Department of Environmental Medicine, Faculty of Medicine, University of Rijeka, Rijeka, Croatia

    Luka Traven

Authors
  1. Maja Mitrović
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jurica Arapović
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luka Traven
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Astrid Krmpotić
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stipan Jonjić
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stipan Jonjić.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mitrović, M., Arapović, J., Traven, L. et al. Innate immunity regulates adaptive immune response: lessons learned from studying the interplay between NK and CD8+ T cells during MCMV infection. Med Microbiol Immunol 201, 487–495 (2012). https://doi.org/10.1007/s00430-012-0263-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-012-0263-0

Keywords

Search

Navigation