Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C

PLoS Pathog. 2013;9(6):e1003422. doi: 10.1371/journal.ppat.1003422. Epub 2013 Jun 20.


Loss of CD4 T cell help correlates with virus persistence during acute hepatitis C virus (HCV) infection, but the underlying mechanism(s) remain unknown. We developed a combined proliferation/intracellular cytokine staining assay to monitor expansion of HCV-specific CD4 T cells and helper cytokines expression patterns during acute infections with different outcomes. We demonstrate that acute resolving HCV is characterized by strong Th1/Th17 responses with specific expansion of IL-21-producing CD4 T cells and increased IL-21 levels in plasma. In contrast, viral persistence was associated with lower frequencies of IL-21-producing CD4 T cells, reduced proliferation and increased expression of the inhibitory receptors T cell immunoglobulin and mucin-domain-containing-molecule-3 (Tim-3), programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) on HCV-specific CD8 T cells. Progression to persistent infection was accompanied by increased plasma levels of the Tim-3 ligand Galectin-9 (Gal-9) and expansion of Gal-9 expressing regulatory T cells (Tregs). In vitro supplementation of Tim-3(high) HCV-specific CD8 T cells with IL-21 enhanced their proliferation and prevented Gal-9 induced apoptosis. siRNA-mediated knockdown of Gal-9 in Treg cells rescued IL-21 production by HCV-specific CD4 T cells. We propose that failure of CD4 T cell help during acute HCV is partially due to an imbalance between Th17 and Treg cells whereby exhaustion of both CD4 and CD8 T cells through the Tim-3/Gal-9 pathway may be limited by IL-21 producing Th17 cells or enhanced by Gal-9 producing Tregs.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Proliferation*
  • Cells, Cultured
  • Female
  • Follow-Up Studies
  • Galectins / biosynthesis
  • Galectins / immunology*
  • Gene Expression Regulation / immunology
  • Hepatitis A Virus Cellular Receptor 2
  • Hepatitis C / blood
  • Hepatitis C / immunology*
  • Hepatitis C / pathology
  • Humans
  • Interleukins / blood
  • Interleukins / immunology*
  • Male
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / pathology
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism
  • Th17 Cells / pathology


  • Galectins
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Interleukins
  • LGALS9 protein, human
  • Membrane Proteins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • interleukin-21