Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C

• Published in: Gut Vol. 55; no. 6; pp. 869 - 877
• Main Authors: Nattermann, J, Feldmann, G, Ahlenstiel, G, Langhans, B, Sauerbruch, T, Spengler, U
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.06.2006; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Adult; Aged; Antigens; Antiviral Agents - therapeutic use; Biological and medical sciences; CD8+ T cells; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Cytokines; Cytotoxicity, Immunologic; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genotype & phenotype; HBV; HCV; Hemophilia; Hepatitis; Hepatitis B virus; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - immunology; HIV; HLA-E; Human immunodeficiency virus; Human viral diseases; Humans; Immune Tolerance; immunodeficiency virus; Infections; Infectious diseases; Interferon; Killer Cells, Natural - immunology; Ligands; Liver Disease; Lymphocytes; major histocompatibility complex class; Male; Medical sciences; Membrane Glycoproteins - blood; MHC; Middle Aged; natural cytotoxicity receptors; Natural Cytotoxicity Triggering Receptor 1; Natural Cytotoxicity Triggering Receptor 2; Natural Cytotoxicity Triggering Receptor 3; natural killer; natural killer cell receptors; natural killer cells; NCR; NK cell receptors; NKR; Receptors, Immunologic - blood; recombinant interleukin 2; rIL-2; T cell receptor; T cell receptors; TCR; TGF-β; transforming growth factor β; Viral diseases; Viral hepatitis; Viruses; Germany; Infection; Natural killer cell; Viral disease; Gastroenterology; Digestive diseases; Hepatic disease; Viral hepatitis C
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2005.076463

Introduction: Impaired activity of natural killer (NK) cells has been proposed as a mechanism contributing to viral persistence in hepatitis C virus (HCV) infection. As the function of NK cells is primarily regulated by NK cell receptors (NKR), we analysed whether decreased NK cell function in hepatitis C may be related to dysregulated NKR expression. Patients and methods: Expression of NK cell was analysed by flow cytometry on lymphocytes from HCV(+) subjects (n = 30), patients who became HCV(−) after antiviral therapy (n = 10), healthy individuals (n = 10), and hepatitis B virus (HBV) infected patients (n = 9). Cytolytic function of lymphocytes was studied in a redirected lysis assay and in a standard 51chromium release cytotoxicity assay, respectively. Results: In patients with chronic hepatitis C, we found a significantly reduced proportion of NKp46 and NKp30 expressing NK cells compared with healthy and HBV infected subjects. Low expression of natural cytotoxicity receptor (NCR) was also confirmed in in vitro activated NK cell populations derived from HCV patients compared with uninfected donors. In contrast, patients who cleared HCV under antiviral therapy showed normal expression of NKp44, NKp30, and NKp46. Reduced NCR expression in chronic hepatitis C was associated with a parallel decrease in NCR mediated target cell killing. Furthermore, we found a significantly increased proportion of NKG2A expressing NK cells and CD8+ T cells in HCV positive patients, resulting in a reduced cytolytic activity against cells incubated with the HLA-E stabilising peptide HCV core35–44. Conclusion: The present study indicates that defective expression of NKR represents a novel mechanism contributing to impaired function of NK cells and CD8+ T cells in chronic hepatitis C.