A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection

PLoS One. 2010 Mar 4;5(3):e9504. doi: 10.1371/journal.pone.0009504.


Approximately 200 million people throughout the world are infected with hepatitis C virus (HCV). One of the most striking features of HCV infection is its high propensity to establish persistence (approximately 70-80%) and progressive liver injury. Galectins are evolutionarily conserved glycan-binding proteins with diverse roles in innate and adaptive immune responses. Here, we demonstrate that galectin-9, the natural ligand for the T cell immunoglobulin domain and mucin domain protein 3 (Tim-3), circulates at very high levels in the serum and its hepatic expression (particularly on Kupffer cells) is significantly increased in patients with chronic HCV as compared to normal controls. Galectin-9 production from monocytes and macrophages is induced by IFN-gamma, which has been shown to be elevated in chronic HCV infection. In turn, galectin-9 induces pro-inflammatory cytokines in liver-derived and peripheral mononuclear cells; galectin-9 also induces anti-inflammatory cytokines from peripheral but not hepatic mononuclear cells. Galectin-9 results in expansion of CD4(+)CD25(+)FoxP3(+)CD127(low) regulatory T cells, contraction of CD4(+) effector T cells, and apoptosis of HCV-specific CTLs. In conclusion, galectin-9 production by Kupffer cells links the innate and adaptive immune response, providing a potential novel immunotherapeutic target in this common viral infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • CD4 Antigens / biosynthesis
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Forkhead Transcription Factors / biosynthesis
  • Galectins / metabolism*
  • Gene Expression Regulation, Viral*
  • Hepacivirus / metabolism*
  • Hepatitis C / metabolism*
  • Humans
  • Immunotherapy / methods
  • Interferon-gamma / metabolism
  • Interleukin-2 Receptor alpha Subunit / biosynthesis
  • Interleukin-7 Receptor alpha Subunit / biosynthesis
  • Kupffer Cells / metabolism*
  • Leukocytes, Mononuclear / cytology
  • Ligands
  • Macrophages / metabolism
  • Monocytes / metabolism
  • T-Lymphocytes / immunology*


  • CD4 Antigens
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Galectins
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-7 Receptor alpha Subunit
  • LGALS9 protein, human
  • Ligands
  • Interferon-gamma