title: Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis.
abstract: Natural killer (NK) cells play a role in the early control and natural course of hepatitis C virus (HCV) infection. NK cell function is regulated by a multitude of receptors, including activating NKp46 receptor. However, reports on NKp46 in hepatitis C are controversial. Therefore, we investigated the hepatic recruitment and function of NKp46(+) NK cells, considering differential surface expression of NKp46 resulting in NKp46(High) and NKp46(Dim) subsets. Intra- and extrahepatic NK-cell subsets from HCV-infected patients were characterized by flow cytometry. Cytotoxic activity and interferon-gamma (IFN-γ) secretion were studied using K-562, P815, and primary hepatic stellate cells as targets. Anti-HCV activity of NK-cell subsets was studied using the replicon system. Density of NKp46 surface expression clearly segregated NKp46(Dim) and NKp46(High) subsets, which differed significantly with respect to the coexpression of maturation markers and NK-cell receptors. More important, NKp46(High) NK cells showed a higher cytolytic activity and stronger IFN-γ secretion than NKp46(Dim) NK cells. Accordingly, NKp46(High) NK cells efficiently blocked HCV replication in vitro. Blocking experiments confirmed an important role for the NKp46 receptor. Furthermore, we found an intrahepatic accumulation of NKp46(High) NK cells. Of note, high cytolytic activity of NKp46(High) NK cells was also confirmed in the intrahepatic NK-cell population, and the frequency of intrahepatic NKp46(High) NK cells was inversely correlated with HCV-RNA levels and fibrosis stage.
  
  
  CONCLUSIONS
  NKp46(High) expression defines a specific NK-cell subset that may be involved in both the suppression of HCV replication and HCV-associated liver damage underpinning the role of NK cells in the immunopathogenesis of HCV.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krämer
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
authors.forename: Moritz
authors.initials: M
authors.lastname: Kebschull
authors.forename: Andreas
authors.initials: A
authors.lastname: Glässner
authors.forename: Marianne
authors.initials: M
authors.lastname: Eisenhardt
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Nischalke
authors.forename: Michael
authors.initials: M
authors.lastname: Alexander
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001707:Biopsy, Needle; D016022:Case-Control Studies; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D005234:Fatty Liver / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D005260:Female; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000276:immunology* / Q000472:pathogenicity; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D019693:Hepatitis, Autoimmune / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology / Q000502:physiology; D016014:Linear Models; D008103:Liver Cirrhosis / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics* / Q000378:metabolism; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000235:genetics / Q000276:immunology; D012367:RNA, Viral / Q000235:genetics; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D012367:RNA, Viral