title: The paradox of NKp46+ natural killer cells: drivers of severe hepatitis C virus-induced pathology but in-vivo resistance to interferon α treatment.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: Institute of Infection & Immunity, Cardiff University, , Cardiff, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Pembroke
authors.forename: Adam
authors.initials: A
authors.lastname: Christian
authors.forename: Emma
authors.initials: E
authors.lastname: Jones
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hills
authors.forename: Eddie C Y
authors.initials: EC
authors.lastname: Wang
authors.forename: Awen M
authors.initials: AM
authors.lastname: Gallimore
authors.forename: Andrew
authors.initials: A
authors.lastname: Godkin
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D016022:Case-Control Studies; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000276:immunology*; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D048550:Hepatic Insufficiency / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000378:metabolism*; D016014:Linear Models; D008099:Liver / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism*; D012254:Ribavirin / Q000627:therapeutic use; D012720:Severity of Illness Index; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D016898:Interferon-alpha; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D012254:Ribavirin
keywords: CHRONIC VIRAL HEPATITIS; HEPATITIS C; IMMUNE-MEDIATED LIVER DAMAGE; IMMUNOLOGY IN HEPATOLOGY