title: CD28-negative CD8-positive cytotoxic T lymphocytes mediate hepatocellular damage in hepatitis C virus infection.
abstract: The pathogenic mechanism for hepatocellular damage in hepatitis C virus (HCV) infection has not been clearly understood. Analysis of costimulatory molecules on lymphocytes may give us insight into the pathogenic mechanism of hepatocellular damage in HCV infection. Peripheral blood mononuclear cells (PBMCs) and liver infiltrating mononuclear cells (LIMCs) isolated from the HCV-infected patients were analyzed with antibodies directed against a variety of costimulatory molecules by flow cytometry. Blocking experiment against HLA-A24-restricted HCV-specific CTLs and immunohistochemical analysis were also performed. PBMCs expressing CD8, CD28, CD80, or CD154 were significantly reduced in HCV-infected patients compared with the healthy controls. CD28(+)CD8(+) PBMCs in the patients inversely correlated with ALT levels. Conversely, levels of CD28(-)CD8(+) LIMCs correlated with ALT levels. HCV-specific CTL activity was blocked by the treatment with anti-CD8 antibody, but not with anti-CD4 or anti-CD28 antibody. Immunohistochemical analysis revealed the accumulation of CD28(+) cells around the portal area in the liver of a patient with chronic active hepatitis C. These results suggest that CD28(+)CD8(+) T cells leave the circulation, move to the livers, and are activated in the portal area in proportion to the extent of liver diseases. CD28(-)CD8(+) T cells may finally function as effector T cells causing the hepatocellular damage in HCV infection.
authors.affiliation: Third Department of Internal Medicine, Kagawa Medical University, Kita-gun, Kagawa, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Kurokohchi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
authors.forename: Keiji
authors.initials: K
authors.lastname: Arima
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Miyauchi
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Funaki
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yoneyama
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yoshida
authors.forename: Akihiro
authors.initials: A
authors.lastname: Deguchi
authors.forename: Seiji
authors.initials: S
authors.lastname: Nakai
authors.forename: Seishiro
authors.initials: S
authors.lastname: Watanabe
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuriyama
mesh_terms: D018106:CD28 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D015234:HLA-A Antigens / Q000276:immunology; D059871:HLA-A24 Antigen; D006526:Hepatitis C / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D016827:CD8 Antigens; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen