Research Article | Published:

Hepatic and Pancreatic Systems

Hepatitis B core antigen upregulates B7-H1 on dendritic cells by activating the AKT/ERK/P38 pathway: a possible mechanism of hepatitis B virus persistence

Laboratory Investigation volume 96, pages 11561164 (2016) | Download Citation


B7-H1 binding to programmed death-1 may deliver a coinhibitory signal to T cells that is involved in the regulation of T-cell activation and tolerance. B7-H1 plays a key role in dysfunction of dendritic cells (DCs) during chronic HBV infection, but the expression mechanism of B7-H1 remains unclear. One hundred and twenty-nine patients with chronic HBV infection were categorized into either the immune tolerance phase (HBV-IT), the immune clearance phase (HBV-IC), or the inactive carrier phase (HBV-IA). Twenty healthy volunteers were enrolled as controls. Another 16 patients with HBeAg-positive chronic Hepatitis B were enrolled, and entecavir was administrated at 0.5 mg per day for 6 months. The B7-H1 expression level on peripheral DCs was tested by flow cytometry. In vitro, expression levels of B7-H1 and signaling molecules on monocyte-derived DC (MO-DC) induced by recombinant hepatitis B virus C antigen (rhHBcAg) were examined by RT-PCR, flow cytometry, and western blotting, and the apoptosis rate was tested by flow cytometry. The percentages of peripheral DCs and myeloid DCs (mDCs) were decreased and B7-H1 levels were increased in patients compared with controls. Serum HBV-DNA levels were positively correlated with B7-H1 levels on mDCs in patients with HBV-IT. B7-H1 levels on peripheral DCs from patients with chronic hepatitis B decreased after antiviral therapy. In vitro studies demonstrated that the B7-H1 level on MO-DC was upregulated by rhHBcAg, which resulted from the activation of PI3K–AKT, ERK, and P38 signaling pathways, and the percentage of MO-DC was downregulated by rhHBcAg. In addition, rhHBcAg promoted the apoptosis of MO-DC. The data suggest that HBcAg induced B7-H1 upregulation by activating AKT, ERK, and P38 signaling pathways, which inhibited the clearance of HBV-DNA and the reduction of DCs contributed to immune tolerance, which may correlate with apoptosis.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , . Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatology 2013;57:399–408.

  2. 2.

    , , et al. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J Hepatol 2016;62:956–967.

  3. 3.

    , , et al. The direct and indirect roles of HBV in liver cancer: prospective markers for HCC screening and potential therapeutic targets. J Pathol 2016;235:355–367.

  4. 4.

    , . Immune response and tolerance during chronic hepatitis B virus infection. Hepatol Res 2007;37(Suppl 3):S331–S338.

  5. 5.

    , . Control or persistence of hepatitis B virus: the critical role of initial host-virus interactions. Immunol Cell Biol 2002;80:101–105.

  6. 6.

    , . Chronic hepatitis B. Hepatology 2007;45:507–539.

  7. 7.

    , . Natural history and clinical consequences of hepatitis B virus infection. Int J Med Sci 2005;2:36–40.

  8. 8.

    , . Molecular characteristics and stages of chronic hepatitis B virus infection. World J Gastroenterol 2009;15:3099–3105.

  9. 9.

    , , et al. Dendritic cells in pathogen recognition and induction of immune responses: a functional genomics approach. J Leukoc Biol 2006;79:913–916.

  10. 10.

    . The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991;9:271–296.

  11. 11.

    , , et al. Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B. Hepatology 2004;40:738–746.

  12. 12.

    , , et al. Telbivudine improves the function of myeloid dendritic cells in patients with chronic hepatitis B. Acta Virol 2012;56:31–38.

  13. 13.

    , , et al. Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus. Immunology 2009;126:280–289.

  14. 14.

    . Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 2004;4:336–347.

  15. 15.

    , , et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999;5:1365–1369.

  16. 16.

    , , et al. Cutting edge: programmed death (PD) ligand-1/PD-1 interaction is required for CD8+ T cell tolerance to tissue antigens. J Immunol 2006;177:8291–8295.

  17. 17.

    , , et al. Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation. Eur J Immunol 2006;36:2472–2482.

  18. 18.

    , , et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 2003;170:1257–1266.

  19. 19.

    , , et al. B7-H1 up-regulation on myeloid dendritic cells significantly suppresses T cell immune function in patients with chronic hepatitis B. J Immunol 2007;178:6634–6641.

  20. 20.

    . Inhibitors of the PD-1/PD-L1 pathway can mobilize the immune system: an innovative potential therapy for cancer and chronic infections. ACS Med Chem Lett 2015;6:489–490.

  21. 21.

    , , et al. Regulation of B7-H1 expression on peripheral monocytes and IFN-gamma secretion in T lymphocytes by HBeAg. Cell Immunol 2013;283:25–30.

  22. 22.

    , , et al. HBcAg induces PD-1 upregulation on CD4+T cells through activation of JNK, ERK and PI3K/AKT pathways in chronic hepatitis-B-infected patients. Lab Invest 2012;92:295–304.

  23. 23.

    , . Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 1994;179:1109–1118.

  24. 24.

    , , et al. Origin and differentiation of dendritic cells. Trends Immunol 2001;22:691–700.

  25. 25.

    , , et al. Negative role of inducible PD-1 on survival of activated dendritic cells. J Leukoc Biol 2014;95:621–629.

  26. 26.

    , . Dendritic cells and the control of immunity. Nature 1998;392:245–252.

  27. 27.

    . Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2002;2:957–964.

  28. 28.

    , , et al. Decreased numbers and impaired function of circulating dendritic cell subsets in patients with chronic hepatitis B infection (R2). J Gastroenterol Hepatol 2005;20:234–242.

  29. 29.

    , , et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677–704.

  30. 30.

    , , et al. Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens. Proc Natl Acad Sci USA 2011;108:3677–3682.

  31. 31.

    , , et al. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int Immunol 2009;21:1065–1077.

  32. 32.

    , , et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793–800.

  33. 33.

    , , et al. Interference with PD-L1/PD-1 co-stimulation during antigen presentation enhances the multifunctionality of antigen-specific T cells. Gene Ther 2014;21:262–271.

  34. 34.

    , , et al. Intrahepatic levels of PD-1/PD-L correlate with liver inflammation in chronic hepatitis B. Inflamm Res 2011;60:47–53.

  35. 35.

    , , et al. PD-1 blockage reverses immune dysfunction and hepatitis B viral persistence in a mouse animal model. PLoS One 2012;7:e39179.

Download references


This work was supported by the National Natural Science Foundation of China (81202662, 81473477, 81403354, 81473629, 81403351 and 81503545) and Science Research Project of Twelve Five-year Plan (2012ZX10005004-002) and Three-year action plan of development of TCM in Shanghai (ZYSNXD-CC-ZDYJ015 and ZY3-CCCX-3-3027) and Training plan of outstanding young medical talents, Shanghai Municipal Health Bureau (XYQ2013093).

Author information

Author notes

    • Zhen-Hua Zhou

    These authors contributed equally to this work.


  1. Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China

    • Man Li
    • , Zhen-Hua Zhou
    • , Xin Zhang
    • , Shu-Gen Jin
    • , Ya-Ting Gao
    •  & Yue-Qiu Gao
  2. Department of Hepatopathy, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China

    • Xue-Hua Sun
    • , Xiao-Jun Zhu
    • , Yun Jiang
    •  & Yue-Qiu Gao


  1. Search for Man Li in:

  2. Search for Zhen-Hua Zhou in:

  3. Search for Xue-Hua Sun in:

  4. Search for Xin Zhang in:

  5. Search for Xiao-Jun Zhu in:

  6. Search for Shu-Gen Jin in:

  7. Search for Ya-Ting Gao in:

  8. Search for Yun Jiang in:

  9. Search for Yue-Qiu Gao in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Yue-Qiu Gao.

Supplementary information

About this article

Publication history






Supplementary Information accompanies the paper on the Laboratory Investigation website (

Further reading