Expression of Hepatitis B Virus X Protein in Hepatocytes Suppresses CD8+ T Cell Activity
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CD8+ T cells contribute to the clearance of Hepatitis B virus (HBV) infection and an insufficient CD8+ T cell response may be one of the major factors leading to chronic HBV infection. Since the HBx antigen of HBV can up-regulate cellular expression of several immunomodulatory molecules, we hypothesized that HBx expression in hepatocytes might affect CD8+ T cell activity. Methods: We analyzed the activation and apoptosis of CD8+ T cells co-cultured with primary hepatocytes rendered capable of expressing HBx by recombinant baculovirus infection. Results:Expression of HBx in hepatocytes induced low production of interferon-γ and apoptosis of CD8+ T cells, with no effect on CD8 T cell proliferation. However, transcriptional levels of H-2K, ICAM-1 and PD-1 ligand did not correlate with HBx expression in hepatocytes. Conclusion: Our results suggest that HBx may inhibit CD8+ T cell response by regulation of interferon-γ production and apoptosis.
Abstract
CD8+ T cells contribute to the clearance of Hepatitis B virus (HBV) infection and an insufficient CD8+ T cell response may be one of the major factors leading to chronic HBV infection. Since the HBx antigen of HBV can up-regulate cellular expression of several immunomodulatory molecules, we hypothesized that HBx expression in hepatocytes might affect CD8+ T cell activity. Methods: We analyzed the activation and apoptosis of CD8+ T cells co-cultured with primary hepatocytes rendered capable of expressing HBx by recombinant baculovirus infection. Results:Expression of HBx in hepatocytes induced low production of interferon-γ and apoptosis of CD8+ T cells, with no effect on CD8 T cell proliferation. However, transcriptional levels of H-2K, ICAM-1 and PD-1 ligand did not correlate with HBx expression in hepatocytes. Conclusion: Our results suggest that HBx may inhibit CD8+ T cell response by regulation of interferon-γ production and apoptosis.
참고문헌 (33)
- Fattovich G, "Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors", J Hepatol, 48, pp.335~352 (2008)
- Tovo PA, "Hepatitis B virus and hepatitis C virus infections in children", Curr Opin Infect Dis, 18, pp.261~266 (2005)
- Thimme R, "CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection", J Virol, 77, pp.68~76 (2003)
- Guidotti LG, "Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice", Proc Natl Acad Sci USA, 91, pp.3764~3768 (1994)
- Guidotti LG, "Viral clearance without destruction of infected cells during acute HBV infection", Science, 284, pp.825~829 (1999)
- Rehermann B, "The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis", J Exp Med, 181, pp.1047~1058 (1995)
- Webster GJ, "Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms", Hepatology, 32, pp.1117~1124 (2000)
- Löhr HF, "Quantitative and functional analysis of core-specific T-helper cell and CTL activities in acute and chronic hepatitis B", Liver, 18, pp.405~413 (1998)
- Peng G, "PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients", Mol Immunol, 45, pp.963~970 (2008)
- Wuensch SA, "Local intrahepatic CD8+T cell activation by a non-self-antigen results in full functional differentiation", J Immunol, 177, pp.1689~1697 (2006)
- Klein I, "Complete differentiation of CD8+ T cells activated locally within the transplanted liver", J Exp Med, 203, pp.437~447 (2006)
- John B, "Passive and active mechanisms trap activated CD8+ T cells in the liver", J Immunol, 172, pp.5222~5229 (2004)
- Murray DA, "TNF-alpha controls intrahepatic T cell apoptosis and peripheral T cell numbers", J Immunol, 173, pp.2042~2409 (2004)
- Liu ZX, "Fas-mediated apoptosis causes elimination of virus-specific cytotoxic T cells in the virus-infected liver", J Immunol, 166, pp.3035~3041 (2001)
- Dong H, "B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes", Immunity, 20, pp.327~336 (2004)
- Cougot D, "The hepatitis B virus X protein functionally interacts with CREB-binding protein", p300 in the regulation of CREB-mediated transcription, 2007, pp.282, 4277~4287
- Lee MO, "Hepatitis B virus X protein induced expression of interleukin 18 (IL-18): a potential mechanism for liver injury caused by hepatitis B virus (HBV) infection", J Hepatol, 37, pp.380~386 (2002)
- Lara-Pezzi E, "The hepatitis B virus X protein up-regulates tumor necrosis factor alpha gene expression in hepatocytes", Hepatology, 28, pp.1013~1021 (1998)
- Han J, "Selective transcriptional regulations in the human liver cell by hepatitis B viral X protein", Biochem Biophys Res Commun, 272, pp.525~530 (2000)
- Hu KQ, "Up-regulation of intercellular adhesion molecule 1 transcription by hepatitis B virus X protein", Proc Natl Acad Sci USA, 89, pp.11441~11445 (1992)
- Zhou DX, "Activation of class I major histocompatibility complex gene expression by hepatitis B virus", J Virol, 64, pp.4025~4028 (1990)
- Kim SY, "Hepatitis B virus X protein sensitizes UV-induced apoptosis by transcriptional transactivation of Fas ligand gene expression", IUBMB Life, 57, pp.651~658 (2005)
- 진영희, "Expression of Hepatitis C Virus Core Protein in Hepatocytes Does Not Modulate Proliferation or Apoptosis of CD8+ T Cells", Yonsei Medical Journal, 46(6), pp.827~834 (2005), 연세대학교의과대학
- Park OY, "Characterization and gene cloning of monoclonal antibody specific for the hepatitis B virus X protein", Hybridoma, 19, pp.73~80 (2000)
- Valujskikh A, "Cross-primed CD8(+) T cells mediate graft rejection via a distinct effector pathway", Nat Immunol, 3, pp.844~851 (2002)
- Yu DY, "Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein", J Hepatol, 31, pp.123~132 (1999)
- Kondo Y, "Vigorous response of cytotoxic T lymphocytes associated with systemic activation of CD8 T lymphocytes in fulminant hepatitis B", Liver Int, 24, pp.561~567 (2004)
- Iken K, "Apoptosis of activated CD4+ and CD8+ T cells is enhanced by co-culture with hepatocytes expressing hepatitis C virus (HCV) structural proteins through FasL induction", Virology, 46, pp.363~372 (2006)
- Majumder B, "Dendritic cells infected with vpr-positive human immunodeficiency virus type 1 induce CD8+ T-cell apoptosis via upregulation of tumor necrosis factor alpha", J Virol, 81, pp.7388~7399 (2007)
- Radziewicz H, "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, pp.2545~2553 (2007)
- Day CL, "PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression", Nature, 443, pp.350~354 (2006)
- Zhang Z, "Dynamic programmed death 1 expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B", Gastroenterology, 134, pp.1938~1949 (2008)
- Mühlbauer M, "PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis", J Hepatol, 45, pp.520~528 (2006)
