Blockade of Tim-3 signaling restores the virus-specific CD8⁺ T-cell response in patients with chronic hepatitis B

Eur J Immunol. 2012 May;42(5):1180-91. doi: 10.1002/eji.201141852.


Chronic hepatitis B (CHB) is characterized by functionally impaired virus-specific CD8(+) T-cell responses. However, the mechanism underlying this dysfunction has not been fully clarified. We examined the role of a newly identified protein, T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3), in regulating the antiviral CD8(+) T-cell response in CHB patients. Tim-3 expression on peripheral virus-specific CD8(+) T cells from 20 CHB patients and 20 healthy controls was determined by flow cytometry. The phenotypes and cytokine-producing capacity were compared between Tim-3(+) CD8(+) and Tim-3(-) CD8(+) T cells. The impact of Tim-3 signaling on cellular proliferation and cytokine-producing capacity was also studied. Tim-3 expression on hepatitis B virus (HBV)-specific CD8(+) T cells was higher than expression on cytomegalovirus (CMV)-specific CD8(+) T cells. Tim-3(+) CD8(+) T cells exhibited proliferative senescence phenotypes and decreased cytokine production upon antigen challenge. Finally, blocking the Tim-3 pathway significantly improved proliferation and antiviral cytokine secretion of CD8(+) T cells in response to HBV-specific antigen peptides. Tim-3 negatively regulates antiviral responses of CD8(+) T cells isolated from CHB patients, and this response is reversed by blocking the Tim-3 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, Viral / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology*
  • Cell Proliferation
  • Cells, Cultured
  • Cellular Senescence / immunology
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Cytokines / metabolism
  • Cytomegalovirus / immunology
  • Female
  • Hepatitis A Virus Cellular Receptor 2
  • Hepatitis B, Chronic / immunology*
  • Humans
  • Male
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / immunology*
  • Middle Aged
  • Peptides / immunology
  • Signal Transduction / immunology


  • Antigens, Viral
  • Cytokines
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Membrane Proteins
  • Peptides