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OBJECTIVE: There is evidence that natural killer (NK) cells help control persistent viral infections including hepatitis C virus (HCV). The phenotype and function of blood and intrahepatic NK cells, in steady state and after interferon (IFN) α treatment has not been fully elucidated. DESIGN: We performed a comparison of NK cells derived from blood and intrahepatic compartments in multiple paired samples from patients with a variety of chronic liver diseases. Furthermore, we obtained serial paired samples from an average of five time points in HCV patients treated with IFNα. RESULTS: Liver NK cells demonstrate a distinct activated phenotype compared to blood manifested as downregulation of the NK cell activation receptors CD16, NKG2D, and NKp30; with increased spontaneous degranulation and IFN production. In contrast, NKp46 expression was not downregulated. Indeed, NKp46-rich NK populations were the most activated, correlating closely with the severity of liver inflammation. Following initiation of IFNα treatment there was a significant increase in the proportion of intrahepatic NK cells at days 1 and 3. NKp46-rich NK populations demonstrated no reserve activation capacity with IFNα treatment and were associated with poor viral control on treatment and treatment failure. CONCLUSIONS: NKp46 marks out pathologically activated NK cells, which may result from a loss of homeostatic control of activating receptor expression in HCV. Paradoxically these pathological NK cells do not appear to be involved in viral control in IFNα-treated individuals and, indeed, predict slower rates of viral clearance.

Original publication




Journal article



Publication Date





515 - 524


CHRONIC VIRAL HEPATITIS, HEPATITIS C, IMMUNE-MEDIATED LIVER DAMAGE, IMMUNOLOGY IN HEPATOLOGY, Adult, Aged, Antiviral Agents, Biomarkers, Biopsy, Case-Control Studies, Drug Administration Schedule, Drug Resistance, Viral, Drug Therapy, Combination, Female, Flow Cytometry, Hepatic Insufficiency, Hepatitis C, Chronic, Humans, Immunohistochemistry, Interferon-alpha, Killer Cells, Natural, Linear Models, Liver, Lymphocyte Activation, Male, Middle Aged, Natural Cytotoxicity Triggering Receptor 1, Ribavirin, Severity of Illness Index, Treatment Failure, Viral Load