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 Feb;92(2):295-304. doi: 10.1038/labinvest.2011.157. Epub 2011 Oct 31.


Hyper-expression of programmed death-1 (PD-1) is a hallmark of exhausted T cells. In chronic hepatitis-B virus (HBV)-infected patients, PD-1 upregulation on T cells was often observed. The mechanism of it has not been fully understood. In this study, we examined the dynamic changes of PD-1 expression on T cells during the natural history of chronic HBV infection and explored the signaling pathway of PD-1 upregulation by the hepatitis-B core antigen (HBcAg). Sixty-seven chronic HBV-infected patients were categorized into an immune tolerance group, an immune clearance group and an inactive virus carrier group, and 20 healthy volunteers were chosen as normal control group. Peripheral blood mononuclear cells from patients and healthy volunteers, and T lymphocytes from healthy volunteers were separated. Results showed that the PD-1 expression level on CD4(+)T cells in every phase of chronic HBV infection was significantly higher than that in healthy volunteers, whereas such effects were not observed on CD8(+)T cells. In the immune clearance phase, a positive correlation was found between serum HBV DNA level and the PD-1 expression level on CD4(+)T cells. In all phases, no correlation was shown between serum alanine amino transferase (ALT) level and PD-1 expression level. Phosphorylation of JNK, ERK and AKT was induced by HBcAg, and inhibitors of JNK, ERK and PI3K/AKT significantly decreased the HBcAg-induced PD-1 upregulation on CD4(+)T cells. In conclusion, the PD-1 expression level on CD4(+)T cells was upregulated in every phase of chronic HBV infection, which was induced by HBcAg through JNK, ERK and PI3K/AKT signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Base Sequence
  • CD4-Positive T-Lymphocytes
  • Case-Control Studies
  • DNA Primers
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Hepatitis B Core Antigens / physiology*
  • Hepatitis B, Chronic / enzymology
  • Hepatitis B, Chronic / immunology
  • Hepatitis B, Chronic / metabolism*
  • Humans
  • Immune Tolerance
  • MAP Kinase Kinase 4 / metabolism*
  • Male
  • Middle Aged
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Programmed Cell Death 1 Receptor / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation / physiology*
  • Young Adult


  • DNA Primers
  • Hepatitis B Core Antigens
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 4