Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B

Gastroenterology. 2010 Feb;138(2):682-93, 693.e1-4. doi: 10.1053/j.gastro.2009.09.052. Epub 2009 Sep 30.


Background & aims: The antiviral function of peripheral hepatitis B virus (HBV)-specific T cells can be increased in patients with chronic hepatitis B by blocking the interaction of programmed death (PD)-1 with its ligand PD-L1. However, no information is available about the effects of this blockade on intrahepatic lymphocytes. We studied T-cell exhaustion and the effects of PD-1/PD-L1 blockade on intrahepatic and circulating HBV-specific T cells in patients with chronic hepatitis B.

Methods: A total of 42 patients with chronic HBV infection who underwent liver biopsy were studied. The ex vivo phenotype of peripheral and intrahepatic HBV-specific CD8(+) T cells was assessed by flow cytometry with class I tetramers and antibodies to T-cell differentiation molecules. Functional recovery was evaluated by analyzing expansion and production of interferon (IFN)-gamma and interleukin (IL)-2 after short-term incubation of T cells with HBV peptides in the presence of anti-PD-L1 or control antibodies.

Results: Intrahepatic HBV-specific CD8(+) cells expressed higher levels of PD-1 and lower levels of CD127 than their peripheral counterparts. Blockade of PD-1/PD-L1 interaction increased CD8(+) cell proliferation and IFN-gamma and IL-2 production by circulating intrahepatic lymphocytes, even though anti-PD-L1 had a stronger effect on intrahepatic compared with peripheral T cells.

Conclusions: T-cell exhaustion by high antigen concentrations promotes HBV-specific T-cell dysfunction by affecting phenotype and function of peripheral and intrahepatic T cells. By restoring antiviral T-cell functions, not only in peripheral but also in intrahepatic lymphocytes, anti-PD-L1 might be a good therapeutic candidate for chronic HBV infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies / pharmacology
  • Antigens, CD / metabolism
  • Antigens, Viral / immunology
  • Apoptosis Regulatory Proteins / antagonists & inhibitors*
  • Apoptosis Regulatory Proteins / metabolism
  • Biopsy
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / physiology*
  • Cell Proliferation
  • Female
  • Hepatitis B virus / immunology*
  • Hepatitis B, Chronic / metabolism
  • Hepatitis B, Chronic / pathology
  • Hepatitis B, Chronic / physiopathology*
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-2 / metabolism
  • Interleukin-7 Receptor alpha Subunit / metabolism
  • Liver / pathology
  • Liver / physiopathology*
  • Liver / virology*
  • Male
  • Middle Aged
  • Programmed Cell Death 1 Receptor
  • Signal Transduction / physiology


  • Antibodies
  • Antigens, CD
  • Antigens, Viral
  • Apoptosis Regulatory Proteins
  • Interleukin-2
  • Interleukin-7 Receptor alpha Subunit
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma