Skip to content
1887

Journal of General Virology header logo Journal of General Virology

Volume 87, Issue 12

CD8 T cell-mediated immune responses in West Nile virus (Sarafend strain) encephalitis are independent of gamma interferon No Access

Abstract

The flavivirus (WNV) can cause fatal encephalitis in humans and mice. It has recently been demonstrated, in an experimental model using WNV strain Sarafend and C57BL/6 mice, that both virus- and immune-mediated pathology is involved in WNV encephalitis, with CD8 T cells being the dominant subpopulation of lymphocyte infiltrates in the brain. Here, the role of activated WNV-immune CD8 T cells in mouse WNV encephalitis was investigated further. Passive transfer of WNV-immune CD8 T cells reduced mortality significantly and prolonged survival times of mice infected with WNV. Early infiltration of WNV-immune CD8 T cells into infected brains is shown, suggesting a beneficial contribution of these lymphocytes to recovery from encephalitis. This antiviral function was not markedly mediated by gamma interferon (IFN-), as a deficiency in IFN- did not affect mortality to two strains of WNV (Sarafend and Kunjin) or brain virus titres significantly. The cytolytic potential, as well as precursor frequency, of WNV-immune CD8 T cells were not altered by the absence of IFN-. This was reflected in transfer experiments of WNV-immune CD8 T cells from IFN- mice into WNV-infected wild-type mice, which showed that IFN--deficient T cells were as effective as those from WNV-immune wild-type mice in ameliorating disease outcome. It is speculated here that one of the pleiotropic functions of IFN- is mimicked by WNV-Sarafend-mediated upregulation of cell-surface expression of major histocompatibility complex antigens, which may explain the lack of phenotype of IFN- mice in response to WNV.

  • Received:
  • Accepted:
  • Published Online:
SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.81306-0
2006-12-01
2025-01-23
Loading full text...

Full text loading...

References

  1. Alsharifi M., Lobigs M., Simon M. M., Kersten A., Müller K., Koskinen A., Lee E., Müllbacher A. 2006; NK cell-mediated immunopathology during an acute viral infection of the CNS. Eur J Immunol 36:887–896 [CrossRef]
     [Google Scholar]
  2. Bartholdy C., Christensen J. P., Wodarz D., Thomsen A. R. 2000; Persistent virus infection despite chronic cytotoxic T-lymphocyte activation in gamma interferon-deficient mice infected with lymphocytic choriomeningitis virus. J Virol 74:10304–10311 [CrossRef]
     [Google Scholar]
  3. Beasley D. W. C., Li L., Suderman M. T., Barrett A. D. T. 2002; Mouse neuroinvasive phenotype of West Nile virus strains varies depending upon virus genotype. Virology 296:17–23 [CrossRef]
     [Google Scholar]
  4. Bergmann C. C., Parra B., Hinton D. R., Chandran R., Morrison M., Stohlman S. A. 2003; Perforin-mediated effector function within the central nervous system requires IFN- γ -mediated MHC up-regulation. J Immunol 170:3204–3213 [CrossRef]
     [Google Scholar]
  5. Bergmann C. C., Parra B., Hinton D. R., Ramakrishna C., Dowdell K. C., Stohlman S. A. 2004; Perforin and gamma interferon-mediated control of coronavirus central nervous system infection by CD8 T cells in the absence of CD4 T cells. J Virol 78:1739–1750 [CrossRef]
     [Google Scholar]
  6. Biron C. A. 1994; Cytokines in the generation of immune responses to, and resolution of, virus infection. Curr Opin Immunol 6:530–538 [CrossRef]
     [Google Scholar]
  7. Blanden R. V. 1970; Mechanisms of recovery from a generalized viral infection: mousepox. I. The effects of anti-thymocyte serum. J Exp Med 132:1035–1054 [CrossRef]
     [Google Scholar]
  8. Boehm U., Klamp T., Groot M., Howard J. C. 1997; Cellular responses to interferon- γ . Annu Rev Immunol 15:749–795 [CrossRef]
     [Google Scholar]
  9. Cantin E., Tanamachi B., Openshaw H. 1999; Role for gamma interferon in control of herpes simplex virus type 1 reactivation. J Virol 73:3418–3423
     [Google Scholar]
  10. Chambers T. J., Diamond M. S. 2003; Pathogenesis of flavivirus encephalitis. Adv Virus Res 60:273–342
     [Google Scholar]
  11. Dalton D. K., Pitts-Meek S., Keshav S., Figari I. S., Bradley A., Stewart T. A. 1993; Multiple defects of immune cell function in mice with disrupted interferon- γ genes. Science 259:1739–1742 [CrossRef]
     [Google Scholar]
  12. Guidotti L. G., McClary H., Loudis J. M., Chisari F. V. 2000; Nitric oxide inhibits hepatitis B virus replication in the livers of transgenic mice. J Exp Med 191:1247–1252 [CrossRef]
     [Google Scholar]
  13. Halevy M., Akov Y., Ben-Nathan D., Kobiler D., Lachmi B., Lustig S. 1994; Loss of active neuroinvasiveness in attenuated strains of West Nile virus: pathogenicity in immunocompetent and SCID mice. Arch Virol 137:355–370 [CrossRef]
     [Google Scholar]
  14. Hall R. A., Burgess G. W., Kay B. H., Clancy P. 1991; Monoclonal antibodies to Kunjin and Kokobera viruses. Immunol Cell Biol 69:47–49 [CrossRef]
     [Google Scholar]
  15. Henkart P. A. 1994; Lymphocyte-mediated cytotoxicity: two pathways and multiple effector molecules. Immunity 1:343–346 [CrossRef]
     [Google Scholar]
  16. Huang S., Hendriks W., Althage A., Hemmi S., Bluethmann H., Kamijo R., Vilcek J., Zinkernagel R. M., Aguet M. 1993; Immune response in mice that lack the interferon- γ receptor. Science 259:1742–1745 [CrossRef]
     [Google Scholar]
  17. Kagi D., Ledermann B., Burki K., Zinkernagel R. M., Hengartner H. 1995; Lymphocyte-mediated cytotoxicity in vitro and in vivo : mechanisms and significance. Immunol Rev 146:95–115 [CrossRef]
     [Google Scholar]
  18. Karupiah G., Chen J.-H., Mahalingam S., Nathan C. F., MacMicking J. D. 1998a; Rapid interferon γ -dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide synthase 2-deficient mice. J Exp Med 188:1541–1546 [CrossRef]
     [Google Scholar]
  19. Karupiah G., Chen J. H., Nathan C. F., Mahalingam S., MacMicking J. D. 1998b; Identification of Nitric oxide synthase 2 as an innate resistance locus against ectromelia virus infection. J Virol 72:7703–7706
     [Google Scholar]
  20. Kesson A. M., Blanden R. V., Mullbacher A. 1987; The primary in vivo murine cytotoxic T cell response to the flavivirus, West Nile. J Gen Virol 68:2001–2006 [CrossRef]
     [Google Scholar]
  21. King N. J. C., Kesson A. M. 2003; Interaction of flaviviruses with cells of the vertebrate host and decoy of the immune response. Immunol Cell Biol 81:207–216 [CrossRef]
     [Google Scholar]
  22. King N. J. C., Shrestha B., Kesson A. M. 2003; Immune modulation by flaviviruses. Adv Virus Res 60:121–155
     [Google Scholar]
  23. Komatsu T., Bi Z., Reiss C. S. 1996; Interferon- γ induced type I nitric oxide synthase activity inhibits viral replication in neurons. J Neuroimmunol 68:101–108 [CrossRef]
     [Google Scholar]
  24. Landolfo S., Gariglio M., Gribaudo G., Jemma C., Giovarelli M., Cavallo G. 1988; Interferon- γ is not an antiviral, but a growth-promoting factor for T lymphocytes. Eur J Immunol 18:503–509 [CrossRef]
     [Google Scholar]
  25. Licon Luna R. M., Lee E., Mullbacher A., Blanden R. V., Langman R., Lobigs M. 2002; Lack of both Fas ligand and perforin protects from flavivirus-mediated encephalitis in mice. J Virol 76:3202–3211 [CrossRef]
     [Google Scholar]
  26. Liu T., Chambers T. J. 2001; Yellow fever virus encephalitis: properties of the brain-associated T-cell response during virus clearance in normal and gamma interferon-deficient mice and requirement for CD4+ lymphocytes. J Virol 75:2107–2118 [CrossRef]
     [Google Scholar]
  27. Liu Y., King N., Kesson A., Blanden R. V., Müllbacher A. 1988; West Nile virus infection modulates the expression of class I and class II MHC antigens on astrocytes in vitro . Ann N Y Acad Sci 540:483–485 [CrossRef]
     [Google Scholar]
  28. Liu Y., Blanden R. V., Mullbacher A. 1989a; Identification of cytolytic lymphocytes in West Nile virus-infected murine central nervous system. J Gen Virol 70:565–573 [CrossRef]
     [Google Scholar]
  29. Liu Y., King N., Kesson A., Blanden R. V., Mullbacher A. 1989b; Flavivirus infection up-regulates the expression of class I and class II major histocompatibility antigens on and enhances T cell recognition of astrocytes in vitro . J Neuroimmunol 21:157–168 [CrossRef]
     [Google Scholar]
  30. Lobigs M., Müllbacher A., Regner M. 2003a; MHC class I up-regulation by flaviviruses: immune interaction with unknown advantage to host or pathogen. Immunol Cell Biol 81:217–223 [CrossRef]
     [Google Scholar]
  31. Lobigs M., Müllbacher A., Wang Y., Pavy M., Lee E. 2003b; Role of type I and type II interferon responses in recovery from infection with an encephalitic flavivirus. J Gen Virol 84:567–572 [CrossRef]
     [Google Scholar]
  32. Lučin P., Pavić I., Polić B., Jonjić S., Koszinowski U. H. 1992; Gamma interferon-dependent clearance of cytomegalovirus infection in salivary glands. J Virol 66:1977–1984
     [Google Scholar]
  33. Mo X. Y., Tripp R. A., Sangster M. Y., Doherty P. C. 1997; The cytotoxic T-lymphocyte response to Sendai virus is unimpaired in the absence of gamma interferon. J Virol 71:1906–1910
     [Google Scholar]
  34. Momburg F., Müllbacher A., Lobigs M. 2001; Modulation of transporter associated with antigen processing (TAP)-mediated peptide import into the endoplasmic reticulum by flavivirus infection. J Virol 75:5663–5671 [CrossRef]
     [Google Scholar]
  35. Müllbacher A., King N. J. C. 1989; Differential target cell susceptibility to SFV-immune cytotoxic T-cells. Arch Virol 107:97–109 [CrossRef]
     [Google Scholar]
  36. Müllbacher A., Lobigs M. 1995; Up-regulation of MHC class I by flavivirus-induced peptide translocation into the endoplasmic reticulum. Immunity 3:207–214 [CrossRef]
     [Google Scholar]
  37. Müllbacher A., Marshall I. D., Ferris P. 1986; Classification of Barmah Forest virus as an alphavirus using cytotoxic T cell assays. J Gen Virol 67:295–299 [CrossRef]
     [Google Scholar]
  38. Müllbacher A., Lobigs M., Hla R. T., Tran T., Stehle T., Simon M. M. 2002; Antigen-dependent release of IFN- γ by cytotoxic T cells up-regulates Fas on target cells and facilitates exocytosis-independent specific target cell lysis. J Immunol 169:145–150 [CrossRef]
     [Google Scholar]
  39. Müllbacher A., Lobigs M., Lee E. 2003; Immunobiology of mosquito-borne encephalitic flaviviruses. Adv Virus Res 60:87–120
     [Google Scholar]
  40. Müllbacher A., Regner M., Wang Y., Lee E., Lobigs M., Simon M. 2004; Can we really learn from model pathogens?. Trends Immunol 25:524–528 [CrossRef]
     [Google Scholar]
  41. Nagata S. 1997; Apoptosis by death factor. Cell 88:355–365 [CrossRef]
     [Google Scholar]
  42. Nansen A., Jensen T., Christensen J. P., Andreasen S. Ø., Röpke C., Marker O., Thomsen A. R. 1999; Compromised virus control and augmented perforin-mediated immunopathology in IFN- γ -deficient mice infected with lymphocytic choriomeningitis virus. J Immunol 163:6114–6122
     [Google Scholar]
  43. Ou R., Zhou S., Huang L., Moskophidis D. 2001; Critical role for alpha/beta and gamma interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells. J Virol 75:8407–8423 [CrossRef]
     [Google Scholar]
  44. Parra B., Hinton D. R., Marten N. W., Bergmann C. C., Lin M. T., Yang C. S., Stohlman S. A. 1999; IFN- γ is required for viral clearance from central nervous system oligodendroglia. J Immunol 162:1641–1647
     [Google Scholar]
  45. Podack E. R., Hengartner H., Lichtenheld M. G. 1991; A central role of perforin in cytolysis?. Annu Rev Immunol 9:129–157 [CrossRef]
     [Google Scholar]
  46. Ramshaw I. A., Ramsay A. J., Karupiah G., Rolph M. S., Mahalingam S., Ruby J. C. 1997; Cytokines and immunity to viral infections. Immunol Rev 159:119–135 [CrossRef]
     [Google Scholar]
  47. Refaeli Y., Van Parijs L., Alexander S. I., Abbas A. K. 2002; Interferon γ is required for activation-induced death of T lymphocytes. J Exp Med 196:999–1005 [CrossRef]
     [Google Scholar]
  48. Regner M., Müllbacher A., Blanden R. V., Lobigs M. 2001; Immunogenicity of two peptide determinants in the cytolytic T-cell response to flavivirus infection: inverse correlation between peptide affinity for MHC class I and T-cell precursor frequency. Viral Immunol 14:135–149 [CrossRef]
     [Google Scholar]
  49. Rouvier E., Luciani M.-F., Golstein P. 1993; Fas involvement in Ca2+-independent T cell-mediated cytotoxicity. J Exp Med 177:195–200 [CrossRef]
     [Google Scholar]
  50. Sarawar S. R., Cardin R. D., Brooks J. W., Mehrpooya M., Hamilton-Easton A.-M., Mo X. Y., Doherty P. C. 1997; Gamma interferon is not essential for recovery from acute infection with murine gammaherpesvirus 68. J Virol 71:3916–3921
     [Google Scholar]
  51. Scherret J. H., Mackenzie J. S., Hall R. A., Deubel V., Gould E. A. 2002; Phylogeny and molecular epidemiology of West Nile and Kunjin viruses. Curr Top Microbiol Immunol 267:373–390
     [Google Scholar]
  52. Shrestha B., Diamond M. S. 2004; Role of CD8+ T cells in control of West Nile virus infection. J Virol 78:8312–8321 [CrossRef]
     [Google Scholar]
  53. Shrestha B., Samuel M. A., Diamond M. S. 2006a; CD8+ T cells require perforin to clear West Nile virus from infected neurons. J Virol 80:119–129 [CrossRef]
     [Google Scholar]
  54. Shrestha B., Wang T., Samuel M. A., Whitby K., Craft J., Fikrig E., Diamond M. S. 2006b; Gamma interferon plays a crucial early antiviral role in protection against West Nile virus infection. J Virol 80:5338–5348 [CrossRef]
     [Google Scholar]
  55. Smithburn K. C., Hughes T. P., Burke A. W., Paul J. H. 1940; A neurotropic virus isolated from the blood of a native of Uganda. Am J Trop Med Hyg 20:471–492
     [Google Scholar]
  56. Sobek V., Balkow S., Körner H., Simon M. M. 2002; Antigen-induced cell death of T effector cells in vitro proceeds via the Fas pathway, requires endogenous interferon- γ and is independent of perforin and granzymes. Eur J Immunol 32:2490–2499 [CrossRef]
     [Google Scholar]
  57. Taswell C. 1981; Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol 126:1614–1619
     [Google Scholar]
  58. Vassalli P. 1992; The pathophysiology of tumor necrosis factors. Annu Rev Immunol 10:411–452 [CrossRef]
     [Google Scholar]
  59. Wang T., Scully E., Yin Z. & 7 other authors 2003a; IFN- γ -producing γδ T cells help control murine West Nile virus infection. J Immunol 171:2524–2531 [CrossRef]
     [Google Scholar]
  60. Wang Y., Lobigs M., Lee E., Müllbacher A. 2003b; CD8+ T cells mediate recovery and immunopathology in West Nile virus encephalitis. J Virol 77:13323–13334 [CrossRef]
     [Google Scholar]
  61. Wang Y., Lobigs M., Lee E., Müllbacher A. 2004; Exocytosis and Fas mediated cytolytic mechanisms exert protection from West Nile virus induced encephalitis in mice. Immunol Cell Biol 82:170–173 [CrossRef]
     [Google Scholar]
  62. Weiner L. P., Cole G. A., Nathanson N. 1970; Experimental encephalitis following peripheral inoculation of West Nile virus in mice of different ages. J Hyg (Lond) 68:435–446 [CrossRef]
     [Google Scholar]
  63. Wheelock E. F. 1965; Interferon-like virus-inhibitor induced in human leukocytes by phytohemagglutinin. Science 149:310–311 [CrossRef]
     [Google Scholar]
  64. Wong G. H. W., Goeddel D. V. 1986; Tumour necrosis factors α and β inhibit virus replication and synergize with interferons. Nature 323:819–822 [CrossRef]
     [Google Scholar]
  65. Yang Y., Xiang Z., Ertl H. C. J., Wilson J. M. 1995; Upregulation of class I major histocompatibility complex antigens by interferon γ is necessary for T-cell-mediated elimination of recombinant adenovirus-infected hepatocytes in vivo . Proc Natl Acad Sci U S A 92:7257–7261 [CrossRef]
     [Google Scholar]
/content/journal/jgv/10.1099/vir.0.81306-0
Loading
CD8+ T cell-mediated immune responses in West Nile virus (Sarafend strain) encephalitis are independent of gamma interferon
J. Gen. Virol. 87, 3599 (2006); https://doi.org/10.1099/vir.0.81306-0
/content/journal/jgv/10.1099/vir.0.81306-0
/content/journal/jgv/10.1099/vir.0.81306-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error