The immune reactivity role of HCV-induced liver infiltrating lymphocytes in hepatocellular damage

• Published in: Journal of clinical immunology 1997-03, Vol.17 (2), p.140-153
• Main Authors: JIN, Y, FULLER, L, CARRENO, M, ZUCKER, K, ROTH, D, ESQUENAZI, V, KARATZAS, T, SWANSON, S. J, TZAKIS, A. G, MILLER, J
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - immunology; Apoptosis; Apoptosis - immunology; Biological and medical sciences; CD3 antigen; CD3 Complex - immunology; CD4 antigen; CD56 antigen; CD8 antigen; CD95 antigen; Cytokines - metabolism; Cytotoxicity; fas Receptor - metabolism; Hepacivirus - immunology; Hepatitis C - immunology; Hepatocytes; HLA Antigens - metabolism; Human viral diseases; Humans; IL-1β; Immunity, Cellular; Infectious diseases; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - metabolism; Interleukin 2; Interleukin 6; Interleukin 8; Liver; Liver - immunology; Liver Failure - immunology; Liver Failure - pathology; Liver Failure - physiopathology; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medical sciences; Monoclonal antibodies; Phenotype; Receptors, Antigen, T-Cell - metabolism; T-Lymphocyte Subsets - immunology; Tumor necrosis factor-α; Viral diseases; Viral hepatitis; γ-Interferon
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1023/a:1027326415164

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.