Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells

Abstract

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections account for 57% of cases of liver cirrhosis and 78% of cases of primary liver cancer worldwide and cause a million deaths per year. Although HBV and HCV differ in their genome structures, replication strategies and life cycles, they have common features, including their noncytopathic nature and their capacity to induce chronic liver disease, which is thought to be immune mediated. However, the rate of disease progression from chronic hepatitis to cirrhosis varies greatly among infected individuals, and the factors that regulate it are largely unknown. This review summarizes our current understanding of the roles of antigen-specific and nonspecific immune cells in the pathogenesis of chronic hepatitis B and C and discusses recent findings that identify natural killer cells as regulators of T cell function and liver inflammation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Natural history of chronic HBV and HCV infections.
Figure 2: NK cell–mediated lysis of intrahepatic cells involved in the pathogenesis of viral hepatitis.
Figure 3: NK cell–mediated regulation of antiviral T cell responses as observed in the LCMV model of viral hepatitis.
Figure 4: Pathogenesis of HBV-related liver disease.

Similar content being viewed by others

References

  1. Guidotti, L.G. & Chisari, F.V. Immunobiology and pathogenesis of viral hepatitis. Annu. Rev. Pathol. 1, 23–61 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Rehermann, B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J. Clin. Invest. 119, 1745–1754 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rehermann, B. & Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat. Rev. Immunol. 5, 215–229 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Thimme, R. et al. CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J. Virol. 77, 68–76 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Shoukry, N.H. et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J. Exp. Med. 197, 1645–1655 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Boni, C. et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J. Virol. 81, 4215–4225 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schurich, A. et al. Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-prone CD8 T cells in persistent hepatitis B virus infection. Hepatology 53, 1494–1503 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Penna, A. et al. Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 45, 588–601 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Wedemeyer, H. et al. Impaired effector function of hepatitis C virus–specific CD8+ T cells in chronic hepatitis C virus infection. J. Immunol. 169, 3447–3458 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Radziewicz, H. 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. 81, 2545–2553 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. McMahan, R.H. et al. Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J. Clin. Invest. 120, 4546–4557 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bertoletti, A. et al. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature 369, 407–410 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Rehermann, B., Pasquinelli, C., Mosier, S.M. & Chisari, F.V. Hepatitis B virus (HBV) sequence variation of cytotoxic T lymphocyte epitopes is not common in patients with chronic HBV infection. J. Clin. Invest. 96, 1527–1534 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chang, K.M. et al. Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus. J. Clin. Invest. 100, 2376–2385 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Timm, J. et al. Human leukocyte antigen–associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution. Hepatology 46, 339–349 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Wölfl, M. et al. Hepatitis C virus immune escape via exploitation of a hole in the T cell repertoire. J. Immunol. 181, 6435–6446 (2008).

    Article  PubMed  Google Scholar 

  17. Maini, M.K. et al. Direct ex vivo analysis of hepatitis B virus-specific CD8+ T cells associated with the control of infection. Gastroenterology 117, 1386–1396 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Lechner, F. et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J. Exp. Med. 191, 1499–1512 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rehermann, B., Ferrari, C., Pasquinelli, C. & Chisari, F.V. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat. Med. 2, 1104–1108 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Grakoui, A. et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 302, 659–662 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Dazert, E. et al. Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. J. Clin. Invest. 119, 376–386 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim, A.Y. et al. Spontaneous control of HCV is associated with expression of HLA-B 57 and preservation of targeted epitopes. Gastroenterology 140, 686–696.e1 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Fitzmaurice, K. et al. Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection. Gut 60, 1563–1571 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Semmo, N. et al. Maintenance of HCV-specific T-cell responses in antibody-deficient patients a decade after early therapy. Blood 107, 4570–4571 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Takaki, A. et al. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat. Med. 6, 578–582 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. von Hahn, T. et al. Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo. Gastroenterology 132, 667–678 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Stoop, J.N. et al. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 41, 771–778 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Xu, D. et al. Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J. Immunol. 177, 739–747 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Sugimoto, K. et al. Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. Hepatology 38, 1437–1448 (2003).

    PubMed  Google Scholar 

  30. Das, A. et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J. Exp. Med. 205, 2111–2124 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dunn, C. et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell–mediated liver damage. J. Exp. Med. 204, 667–680 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Radziewicz, H. et al. Transient CD86 expression on hepatitis C virus-specific CD8+ T cells in acute infection is linked to sufficient IL-2 signaling. J. Immunol. 184, 2410–2422 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Das, A. et al. IL-10–producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J. Immunol. 189, 3925–3935 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Accapezzato, D. et al. Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection. J. Clin. Invest. 113, 963–972 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Alatrakchi, N. et al. Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor β that can suppress HCV-specific T-cell responses. J. Virol. 81, 5882–5892 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Neumann-Haefelin, C. et al. Human leukocyte antigen B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require compensatory mutations. Hepatology 54, 1157–1166 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Bucks, C.M., Norton, J.A., Boesteanu, A.C., Mueller, Y.M. & Katsikis, P.D. Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion. J. Immunol. 182, 6697–6708 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Mueller, S.N. & Ahmed, R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. USA 106, 8623–8628 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Rutebemberwa, A. 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. 181, 8215–8225 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Jin, Y., Shih, W.K. & Berkower, I. Human T cell response to the surface antigen of hepatitis B virus (HBsAg). Endosomal and nonendosomal processing pathways are accessible to both endogenous and exogenous antigen. J. Exp. Med. 168, 293–306 (1988).

    Article  CAS  PubMed  Google Scholar 

  41. Boni, C. et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 143, 963–973 e9 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Bengsch, B. et al. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog. 6, e1000947 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nakamoto, N. et al. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog. 5, e1000313 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Barber, D.L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Golden-Mason, L. et al. Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J. Virol. 83, 9122–9130 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Raziorrouh, B. et al. The immunoregulatory role of CD244 in chronic hepatitis B infection and its inhibitory potential on virus-specific CD8+ T-cell function. Hepatology 52, 1934–1947 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Schlaphoff, V. et al. Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells. PLoS Pathog. 7, e1002045 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Blackburn, S.D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Mühlbauer, M. et al. PD-L1 is induced in hepatocytes by viral infection and by interferon-α and -γ and mediates T cell apoptosis. J. Hepatol. 45, 520–528 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Iwai, Y., Terawaki, S., Ikegawa, M., Okazaki, T. & Honjo, T. PD-1 inhibits antiviral immunity at the effector phase in the liver. J. Exp. Med. 198, 39–50 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen, C.H. et al. In vivo immune modulatory activity of hepatic stellate cells in mice. Hepatology 44, 1171–1181 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Isogawa, M., Furuichi, Y. & Chisari, F.V. Oscillating CD8+ T cell effector functions after antigen recognition in the liver. Immunity 23, 53–63 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Cao, D. et al. Intrahepatic expression of programmed death-1 and its ligands in patients with HBV-related acute-on-chronic liver failure. Inflammation 36, 110–120 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Wherry, E.J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Grayson, J.M., Weant, A.E., Holbrook, B.C. & Hildeman, D. Role of Bim in regulating CD8+ T-cell responses during chronic viral infection. J. Virol. 80, 8627–8638 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lopes, A.R. et al. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. J. Clin. Invest. 118, 1835–1845 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Larrubia, J.R. et al. Persistent hepatitis C virus (HCV) infection impairs HCV-specific cytotoxic T cell reactivity through Mcl-1/Bim imbalance due to CD127 down-regulation. J. Viral Hepat. 20, 85–94 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Fisicaro, P. et al. Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV. Gastroenterology 143, 1576–1585e.4 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Nakamoto, N. et al. Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 134, 1927–1937, 1937.e1–2 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Manigold, T. et al. Foxp3+CD4+CD25+ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C. Blood 107, 4424–4432 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Peppa, D. et al. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog. 6, e1001227 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dolganiuc, A. et al. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-α and plasmacytoid dendritic cell loss in chronic HCV infection. J. Immunol. 177, 6758–6768 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Tu, Z. et al. TLR-dependent cross talk between human Kupffer cells and NK cells. J. Exp. Med. 205, 233–244 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Duramad, O. et al. IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences. Blood 102, 4487–4492 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Groux, H., Bigler, M., de Vries, J.E. & Roncarolo, M.G. Inhibitory and stimulatory effects of IL-10 on human CD8+ T cells. J. Immunol. 160, 3188–3193 (1998).

    CAS  PubMed  Google Scholar 

  66. Losikoff, P.T., Self, A.A. & Gregory, S.H. Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C. Virulence 3, 610–620 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Cox, A.L. et al. Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C. Hepatology 42, 104–112 (2005).

    Article  PubMed  Google Scholar 

  68. Callendret, B. et al. Transmission of clonal hepatitis C virus genomes reveals the dominant but transitory role of CD8+ T cells in early viral evolution. J. Virol. 85, 11833–11845 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Aubert, R.D. et al. Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection. Proc. Natl. Acad. Sci. USA 108, 21182–21187 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Han, S., Asoyan, A., Rabenstein, H., Nakano, N. & Obst, R. Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery. Proc. Natl. Acad. Sci. USA 107, 20453–20458 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Fuller, M.J. et al. Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection. Hepatology 51, 378–387 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Norris, S. et al. Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J. Hepatol. 28, 84–90 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Bonorino, P. et al. Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C. J. Hepatol. 51, 458–467 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Oliviero, B. et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 137, 1151–1160, 1160.e1–7 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Morishima, C. et al. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology 43, 573–580 (2006).

    Article  PubMed  Google Scholar 

  76. Grégoire, C. et al. The trafficking of natural killer cells. Immunol. Rev. 220, 169–182 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Paust, S. et al. Critical role for the chemokine receptor CXCR6 in NK cell–mediated antigen-specific memory of haptens and viruses. Nat. Immunol. 11, 1127–1135 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. O'Leary, J.G., Goodarzi, M., Drayton, D.L. & von Andrian, U.H. T cell– and B cell–independent adaptive immunity mediated by natural killer cells. Nat. Immunol. 7, 507–516 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Nattermann, J. et al. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut 55, 869–877 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Varchetta, S. et al. Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection. Hepatology 56, 841–849 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Ahlenstiel, G. et al. Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-α–dependent manner. Gastroenterology 138, 325–335.e1–2 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. De Maria, A. et al. Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients. Eur. J. Immunol. 37, 445–455 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Tjwa, E.T., van Oord, G.W., Hegmans, J.P., Janssen, H.L. & Woltman, A.M. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J. Hepatol. 54, 209–218 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Takahashi, K. et al. Plasmacytoid dendritic cells sense hepatitis C virus–infected cells, produce interferon, and inhibit infection. Proc. Natl. Acad. Sci. USA 107, 7431–7436 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Lau, D.T. et al. innate immune tolerance and the role of Kupffer cells in differential responses to interferon therapy among patients with HCV genotype 1 infection. Gastroenterology 144, 402–413.e12 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Nguyen, K.B. et al. Interferon α/β–mediated inhibition and promotion of interferon gamma: STAT1 resolves a paradox. Nat. Immunol. 1, 70–76 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Miyagi, T. et al. High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells. J. Exp. Med. 204, 2383–2396 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Edlich, B. et al. Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients. Hepatology 55, 39–48 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Miyagi, T. et al. Altered interferon-α-signaling in natural killer cells from patients with chronic hepatitis C virus infection. J. Hepatol. 53, 424–430 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Ahlenstiel, G. et al. Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C. Gastroenterology 141, 1231–1239, 1239.e1–2 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Bozzano, F. et al. Activating NK cell receptor expression/function (NKp30, NKp46, DNAM-1) during chronic viraemic HCV infection is associated with the outcome of combined treatment. Eur. J. Immunol. 41, 2905–2914 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Oliviero, B. et al. Natural killer cell dynamic profile is associated with treatment outcome in patients with chronic HCV infection. J. Hepatol. published online, http://dx.doi.org/10.1016/j.jhep.2013.03.003 (14 March 2013).

  93. He, X.S. et al. Global transcriptional response to interferon is a determinant of HCV treatment outcome and is modified by race. Hepatology 44, 352–359 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. McGilvray, I. et al. Hepatic cell-type specific gene expression better predicts HCV treatment outcome than IL28B genotype. Gastroenterology 142, 1122–1131.e1 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Sarasin-Filipowicz, M. et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc. Natl. Acad. Sci. USA 105, 7034–7039 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment–induced viral clearance. Nature 461, 399–401 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Tanaka, Y. et al. Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat. Genet. 41, 1105–1109 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Suppiah, V. et al. IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. Nat. Genet. 41, 1100–1104 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Prokunina-Olsson, L. et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat. Genet. 45, 164–171 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Golden-Mason, L. et al. Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C. Hepatology 54, 1559–1569 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Ando, K. et al. Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J. Exp. Med. 178, 1541–1554 (1993).

    Article  CAS  PubMed  Google Scholar 

  102. Cavanaugh, V.J., Guidotti, L.G. & Chisari, F.V. Interleukin-12 inhibits hepatitis B virus replication in transgenic mice. J. Virol. 71, 3236–3243 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Heise, T., Guidotti, L.G., Cavanaugh, V.J. & Chisari, F.V. Hepatitis B virus RNA-binding proteins associated with cytokine-induced clearance of viral RNA from the liver of transgenic mice. J. Virol. 73, 474–481 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Heise, T., Guidotti, L.G. & Chisari, F.V. Characterization of nuclear RNases that cleave hepatitis B virus RNA near the La protein binding site. J. Virol. 75, 6874–6883 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Jo, J. et al. Analysis of CD8+ T-cell–mediated inhibition of hepatitis C virus replication using a novel immunological model. Gastroenterology 136, 1391–1401 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Guidotti, L.G. et al. Viral clearance without destruction of infected cells during acute HBV infection. Science 284, 825–829 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Shin, E.C. et al. Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection. J. Clin. Invest. 116, 3006–3014 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Webster, G.J. et al. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 32, 1117–1124 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Thimme, R. et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J. Exp. Med. 194, 1395–1406 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Shoukry, N.H., Sidney, J., Sette, A. & Walker, C.M. Conserved hierarchy of helper T cell responses in a chimpanzee during primary and secondary hepatitis C virus infections. J. Immunol. 172, 483–492 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Fisicaro, P. et al. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut 58, 974–982 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Dunn, C. et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology 137, 1289–1300 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Yoon, J.C., Shiina, M., Ahlenstiel, G. & Rehermann, B. Natural killer cell function is intact after direct exposure to infectious hepatitis C virions. Hepatology 49, 12–21 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Crotta, S., Brazzoli, M., Piccioli, D., Valiante, N.M. & Wack, A. Hepatitis C virions subvert natural killer cell activation to generate a cytokine environment permissive for infection. J. Hepatol. 52, 183–190 (2010).

    Article  CAS  PubMed  Google Scholar 

  115. Sène, D. et al. Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. PLoS Pathog. 6, e1001184 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Yoon, J.C., Lim, J.B., Park, J.H. & Lee, J.M. Cell-to-cell contact with hepatitis C virus-infected cells reduces functional capacity of natural killer cells. J. Virol. 85, 12557–12569 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Bukowski, J.F., Woda, B.A., Habu, S., Okumura, K. & Welsh, R.M. Natural killer cell depletion enhances virus synthesis and virus-induced hepatitis in vivo. J. Immunol. 131, 1531–1538 (1983).

    CAS  PubMed  Google Scholar 

  118. Welsh, R.M. & Waggoner, S.N. NK cells controlling virus-specific T cells: rheostats for acute vs. persistent infections. Virology 435, 37–45 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Waggoner, S.N., Cornberg, M., Selin, L.K. & Welsh, R.M. Natural killer cells act as rheostats modulating antiviral T cells. Nature 481, 394–398 (2012).

    Article  CAS  Google Scholar 

  120. Waggoner, S.N., Taniguchi, R.T., Mathew, P.A., Kumar, V. & Welsh, R.M. Absence of mouse 2B4 promotes NK cell–mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis. J. Clin. Invest. 120, 1925–1938 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Cook, K.D. & Whitmire, J.K. The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection. J. Immunol. 190, 641–649 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Lang, P.A. et al. Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proc. Natl. Acad. Sci. USA 109, 1210–1215 (2012).

    Article  PubMed  Google Scholar 

  123. Rabinovich, B.A. et al. Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells. J. Immunol. 170, 3572–3576 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Peppa, D. et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell–mediated deletion. J. Exp. Med. 210, 99–114 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Raué, H.P., Beadling, C., Haun, J. & Slifka, M.K. Cytokine-mediated programmed proliferation of virus-specific CD8+ memory T cells. Immunity 38, 131–139 (2013).

    Article  CAS  PubMed  Google Scholar 

  126. Friedman, S.L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. Winau, F., Quack, C., Darmoise, A. & Kaufmann, S.H. Starring stellate cells in liver immunology. Curr. Opin. Immunol. 20, 68–74 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Radaeva, S. et al. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand–dependent manners. Gastroenterology 130, 435–452 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Melhem, A. et al. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J. Hepatol. 45, 60–71 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Taimr, P. et al. Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis. Hepatology 37, 87–95 (2003).

    Article  CAS  PubMed  Google Scholar 

  131. Glässner, A. et al. NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab. Invest. 92, 967–977 (2012).

    Article  CAS  PubMed  Google Scholar 

  132. Krämer, B. et al. NKp46high expression defines a NK cell subset that is potentially involved in control of HCV replication and modulation of liver fibrosis. Hepatology 56, 1201–1213 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Gur, C. et al. NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut 61, 885–893 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Heise, T., Guidotti, L.G. & Chisari, F.V. La autoantigen specifically recognizes a predicted stem-loop in hepatitis B virus RNA. J. Virol. 73, 5767–5776 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Iannacone, M. et al. Platelets mediate cytotoxic T lymphocyte–induced liver damage. Nat. Med. 11, 1167–1169 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kakimi, K. et al. Blocking chemokine responsive to γ-2/interferon (IFN)- γ inducible protein and monokine induced by IFN-γ activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus–specific cytotoxic T lymphocytes. J. Exp. Med. 194, 1755–1766 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sitia, G. et al. MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs. J. Clin. Invest. 113, 1158–1167 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sitia, G. et al. Depletion of neutrophils blocks the recruitment of antigen-nonspecific cells into the liver without affecting the antiviral activity of hepatitis B virus–specific cytotoxic T lymphocytes. Proc. Natl. Acad. Sci. USA 99, 13717–13722 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Nakamoto, Y., Guidotti, L.G., Kuhlen, C.V., Fowler, P. & Chisari, F.V. Immune pathogenesis of hepatocellular carcinoma. J. Exp. Med. 188, 341–350 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Liaw, Y.F. & Chu, C.M. Hepatitis B virus infection. Lancet 373, 582–592 (2009).

    Article  CAS  PubMed  Google Scholar 

  141. Kwon, H. & Lok, A.S. Hepatitis B therapy. Nat. Rev. Gastroenterol. Hepatol. 8, 275–284 (2011).

    Article  CAS  PubMed  Google Scholar 

  142. Dabbouseh, N.M. & Jensen, D.M. Future therapies for chronic hepatitis C. Nat. Rev. Gastroenterol. Hepatol. 10, 268–276 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Zignego, A.L. & Brechot, C. Extrahepatic manifestations of HCV infection: facts and controversies. J. Hepatol. 31, 369–376 (1999).

    Article  CAS  PubMed  Google Scholar 

  144. Milich, D.R. et al. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc. Natl. Acad. Sci. USA 87, 6599–6603 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen, M. et al. Immune tolerance split between hepatitis B virus precore and core proteins. J. Virol. 79, 3016–3027 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Publicover, J. et al. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J. Clin. Invest. 121, 1154–1162 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Kaplan, D.E. et al. Discordant role of CD4 T-cell response relative to neutralizing antibody and CD8 T-cell responses in acute hepatitis C. Gastroenterology 132, 654–666 (2007).

    Article  CAS  PubMed  Google Scholar 

  148. Urbani, S. et al. Acute phase HBV-specific T cell responses associated with HBV persistence after HBV/HCV coinfection. Hepatology 41, 826–831 (2005).

    Article  PubMed  Google Scholar 

  149. Chang, K.M. et al. Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection. Hepatology 33, 267–276 (2001).

    Article  CAS  PubMed  Google Scholar 

  150. Urbani, S. et al. Virus-specific CD8+ lymphocytes share the same effector-memory phenotype but exhibit functional differences in acute hepatitis B and C. J. Virol. 76, 12423–12434 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Asabe, S. et al. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J. Virol. 83, 9652–9662 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Stacey, A.R. et al. Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J. Virol. 83, 3719–3733 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wieland, S., Thimme, R., Purcell, R.H. & Chisari, F.V. Genomic analysis of the host response to hepatitis B virus infection. Proc. Natl. Acad. Sci. USA 101, 6669–6674 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Zeissig, S. et al. Hepatitis B virus–induced lipid alterations contribute to natural killer T cell–dependent protective immunity. Nat. Med. 18, 1060–1068 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Thomas, D.L. et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461, 798–801 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Shin, E.C. et al. Delayed induction, not impaired recruitment, of specific CD8+ T cells causes the late onset of acute hepatitis C. Gastroenterology 141, 686–695, 695.e1 (2011).

    Article  CAS  PubMed  Google Scholar 

  157. Maini, M.K. et al. The role of virus-specific CD8+ cells in liver damage and viral control during persistent hepatitis B virus infection. J. Exp. Med. 191, 1269–1280 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Shetty, S., Lalor, P.F. & Adams, D.H. Lymphocyte recruitment to the liver: molecular insights into the pathogenesis of liver injury and hepatitis. Toxicology 254, 136–146 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Shields, P.L. et al. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J. Immunol. 163, 6236–6243 (1999).

    CAS  PubMed  Google Scholar 

  160. Tan, A.T. et al. A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B. J. Hepatol. 52, 330–339 (2010).

    Article  CAS  PubMed  Google Scholar 

  161. Rossol, S. et al. Interleukin-12 induction of TH1 cytokines is important for viral clearance in chronic hepatitis B. J. Clin. Invest. 99, 3025–3033 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Webster, G.J. et al. Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy. J. Virol. 78, 5707–5719 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zeremski, M. et al. Peripheral CXCR3-associated chemokines as biomarkers of fibrosis in chronic hepatitis C virus infection. J. Infect. Dis. 200, 1774–1780 (2009).

    Article  CAS  PubMed  Google Scholar 

  164. Zeremski, M. et al. Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C. Hepatology 48, 1440–1450 (2008).

    Article  CAS  PubMed  Google Scholar 

  165. Casrouge, A. et al. Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV. J. Clin. Invest. 121, 308–317 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Barbara Rehermann.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rehermann, B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med 19, 859–868 (2013). https://doi.org/10.1038/nm.3251

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3251

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research