Gastroenterology
Volume 138, Issue 1 , Pages 325-335.e2 , January 2010

Natural Killer Cells Are Polarized Toward Cytotoxicity in Chronic Hepatitis C in an Interferon-Alfa–Dependent Manner

  • Golo Ahlenstiel

      Affiliations

    • Immunology Section, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
    • Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • ,
  • Rachel H. Titerence

      Affiliations

    • Immunology Section, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
    • Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • ,
  • Christopher Koh

      Affiliations

    • Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • ,
  • Birgit Edlich

      Affiliations

    • Immunology Section, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
    • Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • ,
  • Jordan J. Feld

      Affiliations

    • Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • ,
  • Yaron Rotman

      Affiliations

    • Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • ,
  • Marc G. Ghany

      Affiliations

    • Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • ,
  • Jay H. Hoofnagle

      Affiliations

    • Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • ,
  • T. Jake Liang

      Affiliations

    • Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • ,
  • Theo Heller

      Affiliations

    • Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • ,
  • Barbara Rehermann

      Affiliations

    • Immunology Section, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
    • Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
    • Corresponding Author InformationReprint requests Address requests for reprints to: Barbara Rehermann, MD, Chief, Immunology Section, Liver Diseases Branch, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, 10 Center Drive, Building 10, Room 9B16C, Bethesda, Maryland 20892-1800. fax: (301) 402-0491

Received 13 January 2009 ,Accepted 18 August 2009.

References 

  1. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005;5:215–229
  2. Urbani S, Amadei B, Fisicaro P, et al. Heterologous T cell immunity in severe hepatitis C virus infection. J Exp Med. 2005;201:675–680
  3. Lechner F, Wong DK, Dunbar PR, et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med. 2000;191:1499–1512
  4. Chang KM, Thimme R, Melpolder JJ, et al. Differential CD4 and CD8 T-cell responsiveness in hepatitis C virus infection. Hepatology. 2001;33:267–276
  5. Lauer GM, Barnes E, Lucas M, et al. High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology. 2004;127:924–936
  6. Wedemeyer H, He X-S, Nascimbeni M, et al. Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J Immunol. 2002;169:3447–3458
  7. Radziewicz H, Ibegbu CC, Fernandez ML, et al. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol. 2007;81:2545–2553
  8. Rutebemberwa A, Ray SC, Astemborski J, et al. High-programmed death-1 levels on hepatitis C virus-specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection. J Immunol. 2008;181:8215–8225
  9. Norris S, Collins C, Doherty DG, et al. Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J Hepatol. 1998;28:84–90
  10. McIntyre KW, Welsh RM. Accumulation of natural killer and cytotoxic T large granular lymphocytes in the liver during virus infection. J Exp Med. 1986;164:1667–1681
  11. Dunn C, Brunetto M, Reynolds G, et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med. 2007;204:667–680
  12. Khakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science. 2004;305:872–874
  13. Paladino N, Flores AC, Marcos CY, et al. Increased frequencies of activating natural killer receptors are associated with liver injury in individuals who do not eliminate hepatitis C virus. Tissue Antigens. 2007;69(Suppl 1):109–111
  14. Ahlenstiel G, Martin MP, Gao X, et al. Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses. J Clin Invest. 2008;118:1017–1026
  15. Larkin J, Bost A, Glass J, et al. Cytokine-activated NK cells exert direct killing of hepatoma cells harboring hepatitis C virus replicons. J Interferon Cytokine Res. 2006;26:854–865
  16. Golden-Mason L, Madrigal-Estebas L, McGrath E, et al. Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single source exposure. Gut. 2008;57:1121–1128
  17. Morishima C, Paschal DM, Wang CC, et al. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology. 2006;43:573–580
  18. Nattermann J, Feldmann G, Ahlenstiel G, et al. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut. 2006;55:869–877
  19. De Maria A, Fogli M, Mazza S, et al. Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients. Eur J Immunol. 2007;37:445–455
  20. Oliviero B, Varchetta S, Paudice E, et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology. 2009;137:1151–1160
  21. Tseng CT, Klimpel GR. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J Exp Med. 2002;195:43–49
  22. Crotta S, Stilla A, Wack A, et al. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C Virus envelope protein. J Exp Med. 2002;195:35–42
  23. Yoon JC, Shiina M, Ahlenstiel G, et al. Natural killer cell function is intact after direct exposure to infectious hepatitis C virions. Hepatology. 2009;49:12–21
  24. Alter G, Malenfant JM, Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods. 2004;294:15–22
  25. Fehniger TA, Shah MH, Turner MJ, et al. Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response. J Immunol. 1999;162:4511–4520
  26. Saez-Borderias A, Romo N, Magri G, et al. IL-12-dependent inducible expression of the CD94/NKG2A inhibitory receptor regulates CD94/NKG2C+ NK cell function. J Immunol. 2009;182:829–836
  27. Moretta L, Bottino C, Pende D, et al. Human natural killer cells: their origin, receptors and function. Eur J Immunol. 2002;32:1205–1211
  28. Biron CA, Nguyen KB, Pien GC, et al. Natural killer cells in antiviral defence: function and regulation by innate cytokines. Annu Rev Immunol. 1999;17:189–220
  29. Miyagi T, Gil MP, Wang X, et al. High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells. J Exp Med. 2007;204:2383–2396
  30. Meier UC, Owen RE, Taylor E, et al. Shared alterations in NK cell frequency, phenotype, and function in chronic human immunodeficiency virus and hepatitis C virus infections. J Virol. 2005;79:12365–12374
  31. Su AI, Pezacki JP, Wodicka L, et al. Genomic analysis of the host response to hepatitis C virus infection. Proc Natl Acad Sci U S A. 2002;99:15669–15674
  32. Bigger CB, Brasky KM, Lanford RE. DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J Virol. 2001;75:7059–7066
  33. Shin EC, Seifert U, Kato T, et al. Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection. J Clin Invest. 2006;116:3006–3014
  34. Patzwahl R, Meier V, Ramadori G, et al. Enhanced expression of interferon-regulated genes in the liver of patients with chronic hepatitis C virus infection: detection by suppression-subtractive hybridization. J Virol. 2001;75:1332–1338
  35. Liang S, Wei H, Sun R, et al. IFNalpha regulates NK cell cytotoxicity through STAT1 pathway. Cytokine. 2003;23:190–199
  36. Mundt B, Wirth T, Zender L, et al. Tumour necrosis factor related apoptosis inducing ligand (TRAIL) induces hepatic steatosis in viral hepatitis and after alcohol intake. Gut. 2005;54:1590–1596
  37. Lan L, Gorke S, Rau SJ, et al. Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner. J Immunol. 2008;181:4926–4935
  38. Zhu H, Dong H, Eksioglu E, et al. Hepatitis C virus triggers apoptosis of a newly developed hepatoma cell line through antiviral defense system. Gastroenterology. 2007;133:1649–1659
  39. Wang SH, Huang CX, Ye L, et al. Natural killer cells suppress full cycle HCV infection of human hepatocytes. J Viral Hepat. 2008;15:855–864
  40. Thimme R, Bukh J, Spangenberg HC, et al. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci U S A. 2002;99:15661–15668
  41. Guidotti LG, Chisari FV. To kill or to cure: options in host defense against viral infection. Curr Opin Immunol. 1996;8:478–483
  42. Morandi B, Bougras G, Muller WA, et al. NK cells of human secondary lymphoid tissues enhance T cell polarization via IFN-gamma secretion. Eur J Immunol. 2006;36:2394–2400
  43. Feld JJ, Nanda S, Huang Y, et al. Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response. Hepatology. 2007;46:1548–1563

 Conflicts of interest The authors disclose no conflicts.

 Funding This study was supported by the intramural research program of the National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health; and Golo Ahlenstiel is the recipient of grant AH173/1-1 from the Deutsche Forschungsgemein-Schaft, Bonn, Germany.

PII: S0016-5085(09)01559-5

doi: 10.1053/j.gastro.2009.08.066

Gastroenterology
Volume 138, Issue 1 , Pages 325-335.e2 , January 2010