Archivum Immunologiae et Therapiae Experimentalis

, Volume 59, Issue 6, pp 449–455 | Cite as

NK Cells Prevalence, Subsets and Function in Viral Hepatitis C

  • Jan Żeromski
  • Iwona Mozer-Lisewska
  • Mariusz Kaczmarek
  • Arleta Kowala-Piaskowska
  • Jan Sikora
Review
First Online:
Received:
Accepted:

Abstract

Innate immunity appears to play an important role in the pathogenesis of viral hepatitis C. Among various cell subsets of this immunity natural killer (NK) cells raised particular interest. These cells are abundant in liver, possess significant cytotoxic potential and show links with adaptive immunity. They play important role, particularly in the acute phase of viral infections, including hepatitis C. They exhibit various types of receptors, either inhibitory or activating, that are able to react with distinct ligands on infected cells. Homozygosity of some receptors, namely KIR2DL3 reacting with recipient HLA-C1 antigens is a herald of good prognosis in hepatitis C virus (HCV) infection. In the early stage of the latter, both the prevalence and the cytotoxicity of NK cells are increased. Their inhibitory receptors are down regulated whereas activating ones are up regulated. Interferon-γ secreted by NK56+bright NK cells has a direct cytotoxic effect on infected hepatocytes. In contrast, in the chronic phase of HCV liver disease both, the prevalence and function of NK cells are impaired. Nevertheless, their cytotoxicity contributes to liver injury. Cells show change in the polarization profile from NK1 to NK2, manifested by secretion of immunosuppressive cytokines. Some HCV peptides are inhibitory for NK cells leading to the reduction of their antiviral activity. The unwanted effects of HCV peptides can be at least partly reversed by the antiviral therapy.

Keywords

NK cells Viral hepatitis C NK receptors NK cytotoxicity Antiviral therapy HCV-mediated NK immunosuppression 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

This work was supported by the Grant no NN 401535740 from the Polish National Science Centre (to I. Mozer-Lisewska).

Conflict of interest

The authors declare that none of them has any competing interests whatsoever.

References

  1. Abel M, Sene D, Pol S et al (2006) Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection. Hepatology 44:1607–1616PubMedCrossRefGoogle Scholar
  2. Alter G, Jost S, Rihn S et al (2011) Reduced frequencies of NKp30+NKp46+, CD161+ and NKG2D+ NK cells in acute HCV infection may predict viral clearance. J Hepatol 55:278–288PubMedCrossRefGoogle Scholar
  3. Amadei B, Urbani S, Cazaly A et al (2010) Activation of natural killer cells during acute infection with hepatitis C virus. Gastroenterology 138:1536–1545PubMedCrossRefGoogle Scholar
  4. Askar M, Avery R, Corey R et al (2009) Lack of killer immunoglobulin-like receptor 2DS2 (KIR2DS2) and KIR2DL2 is associated with poor responses to therapy of recurrent hepatitis C virus in liver transplant recipients. Liver Transpl 15:1557–1563PubMedCrossRefGoogle Scholar
  5. Björkström NK, Ljunggren HG, Sandberg JK (2010) CD56 negative NK cells: origin, function, and role in chronic viral disease. Trends Immunol 31:401–406PubMedCrossRefGoogle Scholar
  6. Bonorino P, Ramzan M, Camous X et al (2009) Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C. J Hepatol 51:458–467PubMedCrossRefGoogle Scholar
  7. Cheent K, Khakoo SI (2011) Natural killer cells and hepatitis C: action and reaction. Gut 60:268–278PubMedCrossRefGoogle Scholar
  8. Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22:633–640PubMedCrossRefGoogle Scholar
  9. Cox AL, Mosbruger T, Lauer GM et al (2005) Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C. Hepatology 42:104–112PubMedCrossRefGoogle Scholar
  10. Crotta S, Brazzoli M, Piccioli D et al (2010) Hepatitis C virions subvert natural killer cell activation to generate a cytokine environment permissive for infection. J Hepatol 52:183–190PubMedCrossRefGoogle Scholar
  11. Dessouki O, Kamiya Y, Nagahama H et al (2010) Chronic hepatitis C viral infection reduces NK cell frequency and suppresses cytokine secretion: Reversion by anti-viral treatment. Biochem Biophys Res Commun 393:331–337PubMedCrossRefGoogle Scholar
  12. Doherty DG, O’Farrelly C (2000) Innate and adaptive lymphoid cells in the human liver. Immunol Rev 174:5–20PubMedCrossRefGoogle Scholar
  13. Doskali M, Tanaka Y, Ohira M et al (2011) Possibility of adoptive immunotherapy with peripheral blood-derived CD3CD56+ and CD3+CD56+ cells for inducing antihepatocellular carcinoma and antihepatitis C virus activity. J Immunother 34:129–138PubMedCrossRefGoogle Scholar
  14. Fadda L, Borhis G, Ahmed P et al (2010) Peptide antagonism as a mechanism for NK cell activation. Proc Natl Acad Sci USA 107:10160–10165PubMedCrossRefGoogle Scholar
  15. Fathy A, Eldin MM, Metwally L et al (2010) Interferon therapy shifts natural killer subsets among Egyptian patients with chronic hepatitis C. Braz J Infect Dis 14:398–405PubMedCrossRefGoogle Scholar
  16. Fernandez NC, Lozier A, Flament C et al (1999) Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med 5:405–411PubMedCrossRefGoogle Scholar
  17. Gendzekhadze K, Norman PJ, Abi-Rached L et al (2009) Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands. Proc Natl Acad Sci USA 106:18692–18697PubMedCrossRefGoogle Scholar
  18. Gerosa F, Baldani-Guerra B, Nisii C et al (2002) Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 195:327–333PubMedCrossRefGoogle Scholar
  19. Gonzalez VD, Falconer K, Björkström NK et al (2009) Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection: correlation with outcome of pegylated IFN-alpha and ribavirin treatment. J Immunol 183:6612–6618PubMedCrossRefGoogle Scholar
  20. Guidotti LG, Chisari FV (1996) To kill or to cure: options in host defense against viral infection. Curr Opin Immunol 8:478–483PubMedCrossRefGoogle Scholar
  21. Hanabuchi S, Watanabe N, Wang YH et al (2006) Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL). Blood 107:3617–3623PubMedCrossRefGoogle Scholar
  22. Harrison RJ, Ettorre A, Little AM et al (2010) Association of NKG2A with treatment for chronic hepatitis C virus infection. Clin Exp Immunol 161:306–314PubMedGoogle Scholar
  23. Jinushi M, Takehara T, Tatsumi T et al (2003) Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection. J Immunol 171:5423–5429PubMedGoogle Scholar
  24. Jinushi M, Takehara T, Tatsumi T et al (2004) Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol 173:6072–6081PubMedGoogle Scholar
  25. Knapp S, Warshow U, Hegazy D et al (2010) Consistent beneficial effects of killer cell immunoglobulin-like receptor 2DL3 and group 1 human leukocyte antigen-C following exposure to hepatitis C virus. Hepatology 51:1168–1175PubMedCrossRefGoogle Scholar
  26. Lassen MG, Lukens JR, Dolina JS et al (2010) Intrahepatic IL-10 maintains NKG2A + Ly49- liver NK cells in a functionally hyporesponsive state. J Immunol 184:2693–2701PubMedCrossRefGoogle Scholar
  27. Lavanchy D (2009) The global burden of hepatitis C. Liver Int 29(suppl 1):74–81PubMedCrossRefGoogle Scholar
  28. Lee S, Watson MW, Flexman JP et al (2010) Increased proportion of the CD56(bright) NK cell subset in patients chronically infected with hepatitis C virus (HCV) receiving interferon-alpha and ribavirin therapy. J Med Virol 82:568–574PubMedCrossRefGoogle Scholar
  29. Ljunggren HG, Kärre K (1990) In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today 11:237–244PubMedCrossRefGoogle Scholar
  30. Mavilio D, Lombardo G, Kinter A et al (2006) Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection. J Exp Med 203:2339–2350PubMedCrossRefGoogle Scholar
  31. Meier UC, Owen RE, Taylor E et al (2005) Shared alterations in NK cell frequency, phenotype, and function in chronic human immunodeficiency virus and hepatitis C virus infections. J Virol 79:12365–12374PubMedCrossRefGoogle Scholar
  32. Melhem A, Muhanna N, Bishara A et al (2006) Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol 45:60–71PubMedCrossRefGoogle Scholar
  33. Moesta AK, Norman PJ, Yawata M et al (2008) Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C than KIR2DL3. J Immunol 180:3969–3979PubMedGoogle Scholar
  34. Morishima C, Paschal DM, Wang CC et al (2006) Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology 43:573–580PubMedCrossRefGoogle Scholar
  35. Mozer-Lisewska I, Dworacki G, Sluzewski W et al (2007) Alterations in immunophenotype of peripheral blood mononuclear cells in children with chronic viral hepatitis following anti-viral therapy. J Pediatr Infect Dis 2:141–146Google Scholar
  36. Mozer-Lisewska I, Sikora J, Kowala-Piaskowska A et al (2010) The incidence and significance of pattern-recognition receptors in chronic viral hepatitis types B and C in man. Arch Immunol Ther Exp 58:295–302CrossRefGoogle Scholar
  37. Muhanna N, Abu Tair L, Doron S et al (2011) Amelioration of hepatic fibrosis by NK cell activation. Gut 60:90–98PubMedCrossRefGoogle Scholar
  38. Nattermann J, Feldmann G, Ahlenstiel G et al (2006) Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut 55:869–877PubMedCrossRefGoogle Scholar
  39. Oliviero B, Varchetta S, Paudice E et al (2009) Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 137:1151–1160 (1160 e1–7)PubMedCrossRefGoogle Scholar
  40. Paust S, Senman B, von Andrian UH (2010) Adaptive immune responses mediated by natural killer cells. Immunol Rev 235:286–296PubMedGoogle Scholar
  41. Pelletier S, Drouin C, Bédard N et al (2010) Increased degranulation of natural killer cells during acute HCV correlates with the magnitude of virus-specific T cell responses. J Hepatol 53:805–816PubMedCrossRefGoogle Scholar
  42. Peritt D, Robertson S, Gri G et al (1998) Differentiation of human NK cells into NK1 and NK2 subsets. J Immunol 161:5821–5824PubMedGoogle Scholar
  43. Rauch A, Kutalik Z, Descombes P et al (2010) Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 138:1338–1345 (1345 e 1–7)PubMedCrossRefGoogle Scholar
  44. Rehermann B, Nascimbeni M (2005) Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 5:215–229PubMedCrossRefGoogle Scholar
  45. Romero V, Azocar J, Zuniga J et al (2008) Interaction of NK inhibitory receptor genes with HLA-C and MHC class II alleles in Hepatitis C virus infection outcome. Mol Immunol 45:2429–2436PubMedCrossRefGoogle Scholar
  46. Séne D, Levasseur F, Abel M et al (2010) Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. PLoS Pathog 6:e1001184PubMedCrossRefGoogle Scholar
  47. Stegmann KA, Bjorkstrom NK, Veber H et al (2010) Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology 138:1885–1897PubMedCrossRefGoogle Scholar
  48. Sun JC, Lanier LL (2009) Natural killer cells remember: an evolutionary bridge between innate and adaptive immunity? Eur J Immunol 39:2059–2064PubMedCrossRefGoogle Scholar
  49. Thomas DL, Thio CL, Martin MP et al (2009) Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461:798–801PubMedCrossRefGoogle Scholar
  50. Tomasello E, Bléry M, Vély F et al (2000) Signaling pathways engaged by NK cell receptors: double concerto for activating receptors, inhibitory receptors and NK cells. Semin Immunol 12:139–147PubMedCrossRefGoogle Scholar
  51. Vanderkerken K, Bouwens L, De Neve W et al (1993) Origin and differentiation of hepatic natural killer cells (pit cells). Hepatology 18:919–925PubMedCrossRefGoogle Scholar
  52. Wang SH, Huang CX, Ye L et al (2008) Natural killer cells suppress full cycle HCV infection of human hepatocytes. J Viral Hepat 15:855–864PubMedCrossRefGoogle Scholar
  53. Wen F, Brown KE, Britigan BE et al (2008) Hepatitis C core protein inhibits induction of heme oxygenase-1 and sensitizes hepatocytes to cytotoxicity. Cell Biol Toxicol 24:175–188PubMedCrossRefGoogle Scholar
  54. Yoon JC, Shiina M, Ahlenstiel G et al (2009) Natural killer cell function is intact after direct exposure to infectious hepatitis C virions. Hepatology 49:12–21PubMedCrossRefGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2011

Authors and Affiliations

  • Jan Żeromski
    • 1
  • Iwona Mozer-Lisewska
    • 2
  • Mariusz Kaczmarek
    • 1
  • Arleta Kowala-Piaskowska
    • 2
  • Jan Sikora
    • 1
  1. 1.Chair and Department of Clinical ImmunologyUniversity of Medical SciencesPoznanPoland
  2. 2.Chair and Department of Infectious DiseasesUniversity of Medical SciencesPoznanPoland

Personalised recommendations