title: The immune reactivity role of HCV-induced liver infiltrating lymphocytes in hepatocellular damage.
abstract: Liver infiltrating lymphocytes (LIL) were isolated from HCV-positive (+) and HCV-negative (-) end-stage livers. Phenotypic analysis and functional studies using proliferative and lymphocytotoxic assays were performed with the isolated LIL. Two CD3+ lymphocyte populations were found in LIL using FITC anti-CD3 monoclonal antibodies (mAb). One was a bright fluorescence intensity population (as in PBL), and the other dim. We calculated the number of FITC-anti-CD3 mAbs bound per lymphocyte on PBL and LIL and found 80,040 +/- 4628 and 39,615 +/- 3932, respectively. Therefore, HCV+ and HCV- patient PBL contained approximately twice the number of CD3 molecules per cell than patient CD3+ LIL. LIL also contained approximately a threefold higher concentration of TCR alpha beta +, CD4-CD8-, and CD56,16 (NK) cells than the patient PBL. Thus, a major subset of LIL is phenotypically similar to mouse NK1.1+ "intermediate" T cells. LIL freshly isolated from HCV+ livers exhibited weak CTL activity against EBV- or Con A-transformed lymphoblast targets infected with vaccinia-HCV recombinant virus (rHCV) or primary hepatocyte cultured cells. However, after in vitro coculture of LIL with rHCV, these cells developed a strong cytotoxicity for the above targets. In contrast, LIL from HCV- livers were not cytotoxic against the same targets. Histochemical studies (in situ) demonstrated that these hepatocytes express CD95, and stains demonstrated apoptosis. The HCV+ hepatocytes also express class I MHC molecules and ICAM-1. The addition of mAb specific for these adhesion molecules inhibited CML activity. Short-term cultured hepatocytes (targets) from HCV+ and HCV- patients produced low levels of cytokines IL-1 beta, IL-2, IL-6, TNF alpha, and IFN-gamma but a high level of IL-8. It is speculated that LIL expressing reduced numbers of CD3 molecules may even function as immune regulators as proposed for intermediate T cells in mice.
authors.affiliation: University of Miami School of Medicine, Department of Surgery, Florida 33101, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
authors.forename: L
authors.initials: L
authors.lastname: Fuller
authors.forename: M
authors.initials: M
authors.lastname: Carreno
authors.forename: K
authors.initials: K
authors.lastname: Zucker
authors.forename: D
authors.initials: D
authors.lastname: Roth
authors.forename: V
authors.initials: V
authors.lastname: Esquenazi
authors.forename: T
authors.initials: T
authors.lastname: Karatzas
authors.forename: S J
authors.initials: SJ
authors.lastname: Swanson
authors.forename: A G
authors.initials: AG
authors.lastname: Tzakis
authors.forename: J
authors.initials: J
authors.lastname: Miller
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D006680:HLA Antigens / Q000378:metabolism; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008099:Liver / Q000276:immunology; D017093:Liver Failure / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines; D006680:HLA Antigens; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1