title: Liver-derived hepatitis C virus (HCV)-specific CD4(+) T cells recognize multiple HCV epitopes and produce interferon gamma.
abstract: Virus-specific CD4(+) T-cell response at the site of inflammation is believed to play a decisive role for the course of viral disease. In hepatitis C virus (HCV) infection, the majority of studies focused on the peripheral blood T-cell response. In this study we analyzed intrahepatic virus-specific CD4(+) T-cell response and compared this with that in the peripheral blood. Liver and blood-derived T-cell lines were studied in 36 patients (18 with chronic hepatitis C and 18 with HCV-associated cirrhosis). Virus-specific interferon gamma (IFN-gamma) production at a single cell level to various HCV-proteins (core, nonstructural [NS] 3/4, NS5) were determined by enzyme-linked immunospot (ELIspot). Phenotyping was done by fluorescent-activated cell sorter analysis. In approximately half (16 of 36 [44%]) of intrahepatic T-cell lines a significant number of IFN-gamma spots were observed, whereas this was the case in only 19% (7 of 36 T-cell lines) in the blood. In relative terms, core and nonstructural proteins were recognized with the same frequency in both compartments, but HCV-specificity was significantly more often detected in liver tissue compared with the blood. Hepatitis activity index, viral load, and alanine transaminase levels did not correlate with the detection of HCV-specific CD4(+) T cells. All T-cell lines were dominated by CD4(+) T cells. In conclusion, HCV-specific CD4(+) T cells are multispecific, compartmentalize to the liver, and produce IFN-gamma. We speculate that our data would support the concept of compartmentalization of specific T cells at the site of inflammation and that a low frequency of specific T cells is associated with failure to clear the virus and a chronic course of disease.
authors.affiliation: Department of Medicine II, Klinikum Grosshadern, University of Munich, Germany. schirren@med2.med.uni-muenchen.de
authors.forename: C A
authors.initials: CA
authors.lastname: Schirren
authors.forename: M C
authors.initials: MC
authors.lastname: Jung
authors.forename: J T
authors.initials: JT
authors.lastname: Gerlach
authors.forename: T
authors.initials: T
authors.lastname: Worzfeld
authors.forename: G
authors.initials: G
authors.lastname: Baretton
authors.forename: M
authors.initials: M
authors.lastname: Mamin
authors.forename: N
authors.initials: N
authors.lastname: Hubert Gruener
authors.forename: M
authors.initials: M
authors.lastname: Houghton
authors.forename: G R
authors.initials: GR
authors.lastname: Pape
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis; D001773:Blood Cells / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D000939:Epitopes / Q000276:immunology*; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000150:complications / Q000276:immunology / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D008099:Liver / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged
chemical_list: D015415:Biomarkers; D000939:Epitopes; D007371:Interferon-gamma