title: Hepatitis C viral infection is associated with activated cytolytic natural killer cells expressing high levels of T cell immunoglobulin- and mucin-domain-containing molecule-3.
abstract: T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) is an inhibitory receptor implicated in T cell exhaustion characteristic of chronic viral infection. Limited data exist on NK cell Tim-3 expression and functional consequences. In chronic hepatitis C virus (HCV)-infected subjects, we found increased Tim-3 on NKs, which was associated with an activated phenotype. The high level of Tim-3 was not reversed by successful IFN-alpha-based antiviral therapy. Tim-3(high) NK cells up-regulated TRAIL in response to IFN-alpha to a greater extent and demonstrated greater lymphokine-activated killing activity, viral control, and degranulation but similar cytokine production than their Tim-3(low) counterparts. Our results suggest that Tim-3 on NKs is associated with activation of this innate lymphocyte population that is polarized towards cytotoxicity in chronic HCV. These findings reveal roles for Tim-3 in the regulation of NKs that might represent targets for treatment of chronic viral infections.
authors: Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver (UCD), Aurora, CO 80045, USA.
authors: Lucy
authors: L
authors: Golden-Mason
authors: Pediatric Gastroenterology, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA.
authors: Christine E
authors: CE
authors: Waasdorp Hurtado
authors: Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver (UCD), Aurora, CO 80045, USA.
authors: Linling
authors: L
authors: Cheng
authors: Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver (UCD), Aurora, CO 80045, USA; Denver VA Medical Center, Denver, CO, USA. Electronic address: Hugo.Rosen@UCDENVER.edu.
authors: Hugo R
authors: HR
authors: Rosen
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology; D016022:Case-Control Studies; D016207:Cytokines / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology*; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000276:immunology*; D008875:Middle Aged; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D016898:Interferon-alpha; D008565:Membrane Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human
keywords: Cytotoxicity; HCV; Human; IFN-γ; Natural cytotoxicity receptors