1887

Abstract

Human papillomavirus 16 (HPV16) infection causes 50 % or more of cervical cancers in women. The HPV16 E7 oncogene is continuously expressed in infected epithelium with its oncogenicity linked to cervical cancer. The E7 protein is an ideal target in control of HPV infection through T-cell-mediated immunity. Using HPV16 E7-transgenic mouse keratinocytes (KCs–E7) to investigate T-cell-mediated immune responses, we have shown previously that HPV16-encoded E7 protein inhibits IFN-γ-mediated enhancement of MHC class I antigen processing and T-cell-induced target cell lysis. In this study, we found that HPV16 E7 suppresses IFN-γ-induced phosphorylation of STAT1, leading to the blockade of interferon regulatory factor-1 (IRF-1) and transporter associated antigen processing subunit 1 (TAP-1) expression in KCs–E7. The results of a Cr release assay demonstrated that IFN-γ-treated KCs–E7 escaped from CTL recognition because HPV16 E7 downregulated MHC class I antigen presentation on KCs. Restoration of IRF-1 expression in KCs–E7 overcame the inhibitory effect of E7 protein on IFN-γ-mediated CTL lysis and MHC class I antigen presentation on KCs. Our results suggest that HPV16 E7 interferes with the IFN-γ-mediated JAK1/JAK2/STAT1/IRF-1 signal transduction pathway and reduces the efficiency of peptide loading and MHC class I antigen presentation on KCs–E7. These results may reveal a new mechanism whereby HPV16 escapes from immune surveillance .

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2013-11-01
2020-01-18
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References

  1. Ahmad F. , Li P. M. , Meyerovitch J. , Goldstein B. J. . ( 1995; ). Osmotic loading of neutralizing antibodies demonstrates a role for protein-tyrosine phosphatase 1B in negative regulation of the insulin action pathway. . J Biol Chem 270:, 20503–20508. [CrossRef] [PubMed]
    [Google Scholar]
  2. Antonsson A. , Payne E. , Hengst K. , McMillan N. A. . ( 2006; ). The human papillomavirus type 16 E7 protein binds human interferon regulatory factor-9 via a novel PEST domain required for transformation. . J Interferon Cytokine Res 26:, 455–461. [CrossRef] [PubMed]
    [Google Scholar]
  3. Barnabas R. V. , Laukkanen P. , Koskela P. , Kontula O. , Lehtinen M. , Garnett G. P. . ( 2006; ). Epidemiology of HPV 16 and cervical cancer in Finland and the potential impact of vaccination: mathematical modelling analyses. . PLoS Med 3:, e138. [CrossRef] [PubMed]
    [Google Scholar]
  4. Barnard P. , McMillan N. A. . ( 1999; ). The human papillomavirus E7 oncoprotein abrogates signaling mediated by interferon-α. . Virology 259:, 305–313. [CrossRef] [PubMed]
    [Google Scholar]
  5. Berger K. L. , Barriga F. , Lace M. J. , Turek L. P. , Zamba G. J. , Domann F. E. , Lee J. H. , Klingelhutz A. J. . ( 2006; ). Cervical keratinocytes containing stably replicating extrachromosomal HPV-16 are refractory to transformation by oncogenic H-Ras. . Virology 356:, 68–78. [CrossRef] [PubMed]
    [Google Scholar]
  6. Bhat P. , Mattarollo S. R. , Gosmann C. , Frazer I. H. , Leggatt G. R. . ( 2011; ). Regulation of immune responses to HPV infection and during HPV-directed immunotherapy. . Immunol Rev 239:, 85–98. [CrossRef] [PubMed]
    [Google Scholar]
  7. Brucet M. , Marqués L. , Sebastián C. , Lloberas J. , Celada A. . ( 2004; ). Regulation of murine Tap1 and Lmp2 genes in macrophages by interferon gamma is mediated by STAT1 and IRF-1. . Genes Immun 5:, 26–35. [CrossRef] [PubMed]
    [Google Scholar]
  8. Conzelmann M. , Wagner A. H. , Hildebrandt A. , Rodionova E. , Hess M. , Zota A. , Giese T. , Falk C. S. , Ho A. D. . & other authors ( 2010; ). IFN-γ activated JAK1 shifts CD40-induced cytokine profiles in human antigen-presenting cells toward high IL-12p70 and low IL-10 production. . Biochem Pharmacol 80:, 2074–2086. [CrossRef] [PubMed]
    [Google Scholar]
  9. Cordano P. , Gillan V. , Bratlie S. , Bouvard V. , Banks L. , Tommasino M. , Campo M. S. . ( 2008; ). The E6E7 oncoproteins of cutaneous human papillomavirus type 38 interfere with the interferon pathway. . Virology 377:, 408–418. [CrossRef] [PubMed]
    [Google Scholar]
  10. Darji A. , Chakraborty T. , Wehland J. , Weiss S. . ( 1997; ). TAP-dependent major histocompatibility complex class I presentation of soluble proteins using listeriolysin. . Eur J Immunol 27:, 1353–1359. [CrossRef] [PubMed]
    [Google Scholar]
  11. Drew P. D. , Franzoso G. , Carlson L. M. , Biddison W. E. , Siebenlist U. , Ozato K. . ( 1995; ). Interferon regulatory factor-2 physically interacts with NF-κB in vitro and inhibits NF-κB induction of major histocompatibility class I and β2-microglobulin gene expression in transfected human neuroblastoma cells. . J Neuroimmunol 63:, 157–162. [CrossRef] [PubMed]
    [Google Scholar]
  12. Dürst M. , Croce C. M. , Gissmann L. , Schwarz E. , Huebner K. . ( 1987; ). Papillomavirus sequences integrate near cellular oncogenes in some cervical carcinomas. . Proc Natl Acad Sci U S A 84:, 1070–1074. [CrossRef] [PubMed]
    [Google Scholar]
  13. Flores E. R. , Allen-Hoffmann B. L. , Lee D. , Sattler C. A. , Lambert P. F. . ( 1999; ). Establishment of the human papillomavirus type 16 (HPV-16) life cycle in an immortalized human foreskin keratinocyte cell line. . Virology 262:, 344–354. [CrossRef] [PubMed]
    [Google Scholar]
  14. Frazer I. H. . ( 2004; ). Prevention of cervical cancer through papillomavirus vaccination. . Nat Rev Immunol 4:, 46–55. [CrossRef] [PubMed]
    [Google Scholar]
  15. Frazer I. H. . ( 2007; ). HPV immunisation: a significant advance in cancer control. . Gynecol Oncol 107: (Suppl. 1), S1. [CrossRef] [PubMed]
    [Google Scholar]
  16. Frazer I. H. , De Kluyver R. , Leggatt G. R. , Guo H. Y. , Dunn L. , White O. , Harris C. , Liem A. , Lambert P. . ( 2001; ). Tolerance or immunity to a tumor antigen expressed in somatic cells can be determined by systemic proinflammatory signals at the time of first antigen exposure. . J Immunol 167:, 6180–6187.[PubMed] [CrossRef]
    [Google Scholar]
  17. Frazer I. H. , Leggatt G. R. , Mattarollo S. R. . ( 2011; ). Prevention and treatment of papillomavirus-related cancers through immunization. . Annu Rev Immunol 29:, 111–138. [CrossRef] [PubMed]
    [Google Scholar]
  18. Guan P. , Howell-Jones R. , Li N. , Bruni L. , de Sanjosé S. , Franceschi S. , Clifford G. M. . ( 2012; ). Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. . Int J Cancer 131:, 2349–2359. [CrossRef] [PubMed]
    [Google Scholar]
  19. Halbert C. L. , Demers G. W. , Galloway D. A. . ( 1991; ). The E7 gene of human papillomavirus type 16 is sufficient for immortalization of human epithelial cells. . J Virol 65:, 473–478.[PubMed]
    [Google Scholar]
  20. Hammond S. A. , Johnson R. P. , Kalams S. A. , Walker B. D. , Takiguchi M. , Safrit J. T. , Koup R. A. , Siliciano R. F. . ( 1995; ). An epitope-selective, transporter associated with antigen presentation (TAP)-1/2-independent pathway and a more general TAP-1/2-dependent antigen-processing pathway allow recognition of the HIV-1 envelope glycoprotein by CD8+ CTL. . J Immunol 154:, 6140–6156.[PubMed]
    [Google Scholar]
  21. Hong S. , Mehta K. P. , Laimins L. A. . ( 2011; ). Suppression of STAT-1 expression by human papillomaviruses is necessary for differentiation-dependent genome amplification and plasmid maintenance. . J Virol 85:, 9486–9494. [CrossRef] [PubMed]
    [Google Scholar]
  22. Jarosinski K. W. , Massa P. T. . ( 2002; ). Interferon regulatory factor-1 is required for interferon-γ-induced MHC class I genes in astrocytes. . J Neuroimmunol 122:, 74–84. [CrossRef] [PubMed]
    [Google Scholar]
  23. Korkolopoulou P. , Kaklamanis L. , Pezzella F. , Harris A. L. , Gatter K. C. . ( 1996; ). Loss of antigen-presenting molecules (MHC class I and TAP-1) in lung cancer. . Br J Cancer 73:, 148–153. [CrossRef] [PubMed]
    [Google Scholar]
  24. Lace M. J. , Anson J. R. , Klussmann J. P. , Wang D. H. , Smith E. M. , Haugen T. H. , Turek L. P. . ( 2011; ). Human papillomavirus type 16 (HPV-16) genomes integrated in head and neck cancers and in HPV-16-immortalized human keratinocyte clones express chimeric virus-cell mRNAs similar to those found in cervical cancers. . J Virol 85:, 1645–1654. [CrossRef] [PubMed]
    [Google Scholar]
  25. Lambert P. F. , Pan H. , Pitot H. C. , Liem A. , Jackson M. , Griep A. E. . ( 1993; ). Epidermal cancer associated with expression of human papillomavirus type 16 E6 and E7 oncogenes in the skin of transgenic mice. . Proc Natl Acad Sci U S A 90:, 5583–5587. [CrossRef] [PubMed]
    [Google Scholar]
  26. Lee S. H. , Kim J. W. , Lee H. W. , Cho Y. S. , Oh S. H. , Kim Y. J. , Jung C. H. , Zhang W. , Lee J. H. . ( 2003; ). Interferon regulatory factor-1 (IRF-1) is a mediator for interferon-γ induced attenuation of telomerase activity and human telomerase reverse transcriptase (hTERT) expression. . Oncogene 22:, 381–391. [CrossRef] [PubMed]
    [Google Scholar]
  27. Leggatt G. R. , Frazer I. H. . ( 2007; ). HPV vaccines: the beginning of the end for cervical cancer. . Curr Opin Immunol 19:, 232–238. [CrossRef] [PubMed]
    [Google Scholar]
  28. Leggatt G. R. , Dunn L. A. , De Kluyver R. L. , Stewart T. , Frazer I. H. . ( 2002; ). Interferon-gamma enhances cytotoxic T lymphocyte recognition of endogenous peptide in keratinocytes without lowering the requirement for surface peptide. . Immunol Cell Biol 80:, 415–424. [CrossRef] [PubMed]
    [Google Scholar]
  29. Lehtonen A. , Matikainen S. , Julkunen I. . ( 1997; ). Interferons up-regulate STAT1, STAT2, and IRF family transcription factor gene expression in human peripheral blood mononuclear cells and macrophages. . J Immunol 159:, 794–803.[PubMed]
    [Google Scholar]
  30. Li S. , Labrecque S. , Gauzzi M. C. , Cuddihy A. R. , Wong A. H. , Pellegrini S. , Matlashewski G. J. , Koromilas A. E. . ( 1999; ). The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-α. . Oncogene 18:, 5727–5737. [CrossRef] [PubMed]
    [Google Scholar]
  31. Li W. , Deng X. M. , Wang C. X. , Zhang X. , Zheng G. X. , Zhang J. , Feng J. B. . ( 2010; ). Down-regulation of HLA class I antigen in human papillomavirus type 16 E7 expressing HaCaT cells: correlate with TAP-1 expression. . Int J Gynecol Cancer 20:, 227–232. [CrossRef] [PubMed]
    [Google Scholar]
  32. Marquis J. F. , Kapoustina O. , Langlais D. , Ruddy R. , Dufour C. R. , Kim B. H. , MacMicking J. D. , Giguère V. , Gros P. . ( 2011; ). Interferon regulatory factor 8 regulates pathways for antigen presentation in myeloid cells and during tuberculosis. . PLoS Genet 7:, e1002097. [CrossRef] [PubMed]
    [Google Scholar]
  33. Merzougui N. , Kratzer R. , Saveanu L. , van Endert P. . ( 2011; ). A proteasome-dependent, TAP-independent pathway for cross-presentation of phagocytosed antigen. . EMBO Rep 12:, 1257–1264. [CrossRef] [PubMed]
    [Google Scholar]
  34. Mori K. , Stone S. , Khaodhiar L. , Braverman L. E. , DeVito W. J. . ( 1999; ). Induction of transcription factor interferon regulatory factor-1 by interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) in FRTL-5 cells. . J Cell Biochem 74:, 211–219. [CrossRef] [PubMed]
    [Google Scholar]
  35. Münger K. , Howley P. M. . ( 2002; ). Human papillomavirus immortalization and transformation functions. . Virus Res 89:, 213–228. [CrossRef] [PubMed]
    [Google Scholar]
  36. Nakanishi G. , Fujimoto W. , Arata J. . ( 1997; ). IRF-1 expression in normal human epidermal keratinocytes. . Arch Dermatol Res 289:, 415–420. [CrossRef] [PubMed]
    [Google Scholar]
  37. Pamment J. , Ramsay E. , Kelleher M. , Dornan D. , Ball K. L. . ( 2002; ). Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway. . Oncogene 21:, 7776–7785. [CrossRef] [PubMed]
    [Google Scholar]
  38. Park J. S. , Kim E. J. , Kwon H. J. , Hwang E. S. , Namkoong S. E. , Um S. J. . ( 2000; ). Inactivation of interferon regulatory factor-1 tumor suppressor protein by HPV E7 oncoprotein. Implication for the E7-mediated immune evasion mechanism in cervical carcinogenesis. . J Biol Chem 275:, 6764–6769. [CrossRef] [PubMed]
    [Google Scholar]
  39. Perea S. E. , Massimi P. , Banks L. . ( 2000; ). Human papillomavirus type 16 E7 impairs the activation of the interferon regulatory factor-1. . Int J Mol Med 5:, 661–666.[PubMed]
    [Google Scholar]
  40. Romanczuk H. , Villa L. L. , Schlegel R. , Howley P. M. . ( 1991; ). The viral transcriptional regulatory region upstream of the E6 and E7 genes is a major determinant of the differential immortalization activities of human papillomavirus types 16 and 18. . J Virol 65:, 2739–2744.[PubMed]
    [Google Scholar]
  41. Saito H. , Morita Y. , Fujimoto M. , Narazaki M. , Naka T. , Kishimoto T. . ( 2000; ). IFN regulatory factor-1-mediated transcriptional activation of mouse STAT-induced STAT inhibitor-1 gene promoter by IFN-γ. . J Immunol 164:, 5833–5843.[PubMed] [CrossRef]
    [Google Scholar]
  42. Sasagawa T. , Takagi H. , Makinoda S. . ( 2012; ). Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer. . J Infect Chemother 18:, 807–815. [CrossRef] [PubMed]
    [Google Scholar]
  43. Schroder K. , Hertzog P. J. , Ravasi T. , Hume D. A. . ( 2004; ). Interferon-γ: an overview of signals, mechanisms and functions. . J Leukoc Biol 75:, 163–189. [CrossRef] [PubMed]
    [Google Scholar]
  44. Stanley M. A. . ( 2005; ). Establishing HPV-containing keratinocyte cell lines from tissue biopsies. . Methods Mol Med 119:, 129–139.[PubMed]
    [Google Scholar]
  45. Stanley M. A. , Pett M. R. , Coleman N. . ( 2007; ). HPV: from infection to cancer. . Biochem Soc Trans 35:, 1456–1460. [CrossRef] [PubMed]
    [Google Scholar]
  46. Storm van’s Gravesande K. , Layne M. D. , Ye Q. , Le L. , Baron R. M. , Perrella M. A. , Santambrogio L. , Silverman E. S. , Riese R. J. . ( 2002; ). IFN regulatory factor-1 regulates IFN-γ-dependent cathepsin S expression. . J Immunol 168:, 4488–4494.[PubMed] [CrossRef]
    [Google Scholar]
  47. Tennant L. M. , Renard C. , Chardon P. , Powell P. P. . ( 2007; ). Regulation of porcine classical and nonclassical MHC class I expression. . Immunogenetics 59:, 377–389. [CrossRef] [PubMed]
    [Google Scholar]
  48. Tey S. K. , Khanna R. . ( 2012; ). Autophagy mediates transporter associated with antigen processing-independent presentation of viral epitopes through MHC class I pathway. . Blood 120:, 994–1004. [CrossRef] [PubMed]
    [Google Scholar]
  49. Um S. J. , Rhyu J. W. , Kim E. J. , Jeon K. C. , Hwang E. S. , Park J. S. . ( 2002; ). Abrogation of IRF-1 response by high-risk HPV E7 protein in vivo. . Cancer Lett 179:, 205–212. [CrossRef] [PubMed]
    [Google Scholar]
  50. Vambutas A. , DeVoti J. , Pinn W. , Steinberg B. M. , Bonagura V. R. . ( 2001; ). Interaction of human papillomavirus type 11 E7 protein with TAP-1 results in the reduction of ATP-dependent peptide transport. . Clin Immunol 101:, 94–99. [CrossRef] [PubMed]
    [Google Scholar]
  51. Van Doorslaer K. , Burk R. D. . ( 2010; ). Evolution of human papillomavirus carcinogenicity. . Adv Virus Res 77:, 41–62. [CrossRef] [PubMed]
    [Google Scholar]
  52. Wang X. , Liu J. , Zhao W. M. , Zhao K. N. . ( 2009; ). Expression of HPV 58 long and short L1 capsid proteins in primary mouse keratinocyte cultures. . Protein Pept Lett 16:, 65–74. [CrossRef] [PubMed]
    [Google Scholar]
  53. Yewdell J. W. , Snyder H. L. , Bacik I. , Antón L. C. , Deng Y. , Behrens T. W. , Bachi T. , Bennink J. R. . ( 1998; ). TAP-independent delivery of antigenic peptides to the endoplasmic reticulum: therapeutic potential and insights into TAP-dependent antigen processing. . J Immunother 21:, 127–131. [CrossRef] [PubMed]
    [Google Scholar]
  54. Zhou F. . ( 2009a; ). Molecular mechanisms of IFN-gamma to up-regulate MHC class I antigen processing and presentation. . Int Rev Immunol 28:, 239–260. [CrossRef] [PubMed]
    [Google Scholar]
  55. Zhou F. . ( 2009b; ). Molecular mechanisms of viral immune evasion proteins to inhibit MHC class I antigen processing and presentation. . Int Rev Immunol 28:, 376–393. [CrossRef] [PubMed]
    [Google Scholar]
  56. Zhou F. , Frazer I. H. , Leggatt G. R. . ( 2009; ). Keratinocytes efficiently process endogenous antigens for cytotoxic T-cell mediated lysis. . Exp Dermatol 18:, 1053–1059. [CrossRef] [PubMed]
    [Google Scholar]
  57. Zhou F. , Leggatt G. R. , Frazer I. H. . ( 2011; ). Human papillomavirus 16 E7 protein inhibits interferon-γ-mediated enhancement of keratinocyte antigen processing and T-cell lysis. . FEBS J 278:, 955–963. [CrossRef] [PubMed]
    [Google Scholar]
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