title: Liver-infiltrating and circulating CD4+ T cells in chronic hepatitis C: immunodominant epitopes, HLA-restriction and functional significance.
abstract: The aim was to assess the specificity and functional significance of liver-infiltrating and peripheral blood T cells in chronic hepatitis C. Peripheral blood mononuclear cells hepatitis C virus from 50 of 58 (86.2%) patients with chronic hepatitis C virus infection and 6 of 28 (21.4%) controls showed a proliferative T cell response to at least one of 16 synthetic peptides covering highly conserved regions of the core, envelope (El) and non-structural regions (NS4) of hepatitis C virus. However, six immunodominant peptides were exclusively recognized by the proliferating blood mononuclear cells from 46 patients with chronic hepatitis C virus infection (79.3%). Fine specificity and HLA-restriction were studied with 15 peptide-specific CD4+ T cell lines and 23 T cell clones isolated from liver tissue and peripheral blood of 12 patients with chronic hepatitis C. It was demonstrated that the peptide-specific response of CD4+ T cells was restricted to the presence of autologous accessory cells and HLA-DR and -DP molecules. Eight peptide-specific T cell lines and five T cell clones derived from liver tissue and peripheral blood, released interferon-gamma (200-6600 pg/ml) and tumor necrosis factor-alpha (100-400 pg/ml) and no or little interleukin-4 (< 140 pg/ml) after peptide-specific or mitogeneic stimulation, thus resembling a Th1-like cytokine profile. Patients with active liver disease showed significantly higher proliferative responses to hepatitis C virus core peptides than asymptomatic hepatitis C virus carriers or complete responders to interferon therapy. In conclusion, class II-restricted CD4+ T cell responses to some immunodominant epitopes within the hepatitis core region correlated with disease activity in chronic hepatitis C virus infection. Functionally, liver-infiltrating and peripheral blood T cells released Th1-like cytokines in response to the specific stimulus. Thus, it can be suggested that CD4+ T cells can mediate the pathogenesis of chronic hepatitis C virus induced liver disease.
authors.affiliation: 1. Department of Internal Medicine, Johannes-Gutenberg-University, Mainz, Germany.
authors.forename: H F
authors.initials: HF
authors.lastname: Löhr
authors.forename: J F
authors.initials: JF
authors.lastname: Schlaak
authors.forename: S
authors.initials: S
authors.lastname: Kollmannsperger
authors.forename: H P
authors.initials: HP
authors.lastname: Dienes
authors.forename: K H
authors.initials: KH
authors.lastname: Meyer zum Büschenfelde
authors.forename: G
authors.initials: G
authors.lastname: Gerken
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D000939:Epitopes / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology / Q000627:therapeutic use; D015847:Interleukin-4 / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000097:blood; D014170:Transformation, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000939:Epitopes; D006680:HLA Antigens; D008934:Mitogens; D010446:Peptide Fragments; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma