T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B

J Hepatol. 2010 Mar;52(3):322-9. doi: 10.1016/j.jhep.2009.12.005. Epub 2010 Jan 6.


Background & aims: T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been shown to influence autoimmune diseases; however, its function in viral infection has not been well-defined. We therefore investigated the expression and regulatory function of Tim-3 in natural killer (NK) cells in chronic Hepatitis B (CHB) infection.

Methods: Seventy-six CHB patients, 38 healthy controls, and 18 patients with fatty liver disease (FLD) were tested for Tim-3 expression on peripheral blood mononuclear cells (PBMCs) and in the liver tissue by flow cytometry and immunohistochemical stainning. The effects of HBV infection on Tim-3 expression in NK cells and the roles of Tim-3 in regulation of NK-cell function were also studied.

Results: There was a significant increase of Tim-3 expression in PBMCs, circulating NK cells and liver infiltrating lymphocytes (LILs) from CHB patients compared to that of healthy controls and FLD patients. Increased Tim-3 expression was also detected in NK92 cells that had been transfected with a HBV expression vector and NK cells isolated from the liver of HBV transgenic mice. Importantly, blockage of Tim-3 signaling with anti-Tim-3 antibodies or Tim-3-Fc fusion proteins resulted in an increased cytotoxicity for NK92 cells compared to HepG2 and HepG2.2.15 cells, as well as an elevated interferon-gamma (IFN-gamma) production. Similarly, enhanced cytotoxicity was also observed in PBMCs or NK cells from CHB patients treated with the Tim-3 blockade ex vivo.

Conclusion: HBV infection can up-regulate Tim-3 expression in NK cells, which may in turn suppress NK-cell functions in CHB patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Autoantibodies / pharmacology
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / physiopathology
  • Case-Control Studies
  • Cell Line
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fatty Liver / physiopathology
  • Female
  • Hepatitis A Virus Cellular Receptor 2
  • Hepatitis B virus / genetics
  • Hepatitis B virus / physiology
  • Hepatitis B, Chronic / immunology*
  • Hepatitis B, Chronic / pathology
  • Hepatitis B, Chronic / physiopathology*
  • Humans
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / pathology
  • Killer Cells, Natural / physiology*
  • Killer Cells, Natural / virology*
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / pathology
  • Liver / metabolism
  • Liver / pathology
  • Liver / virology
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Liver Neoplasms / physiopathology
  • Lymphocytes / metabolism
  • Lymphocytes / pathology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Middle Aged
  • Retrospective Studies
  • Up-Regulation / physiology


  • Autoantibodies
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Membrane Proteins
  • Interferon-gamma