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

Benjamin Krämer, Christian Körner, Moritz Kebschull, Andreas Glässner, Marianne Eisenhardt, Hans-Dieter Nischalke, Michael Alexander, Tilman Sauerbruch, Ulrich Spengler, Jacob Nattermann

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)


UNLABELLED: 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.

Original languageEnglish
Pages (from-to)1201-13
Number of pages13
Issue number4
Publication statusPublished - Oct 2012

Bibliographical note

Copyright © 2012 American Association for the Study of Liver Diseases.


  • Adolescent
  • Adult
  • Aged
  • Biopsy, Needle
  • Case-Control Studies
  • Cells, Cultured
  • Cytotoxicity, Immunologic/genetics
  • Disease Progression
  • Fatty Liver/genetics
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Viral
  • Hepacivirus/immunology
  • Hepatic Stellate Cells/immunology
  • Hepatitis C, Chronic/genetics
  • Hepatitis, Autoimmune/genetics
  • Humans
  • Immunohistochemistry
  • Killer Cells, Natural/immunology
  • Linear Models
  • Liver Cirrhosis/genetics
  • Liver Function Tests
  • Male
  • Middle Aged
  • Natural Cytotoxicity Triggering Receptor 1/genetics
  • Natural Cytotoxicity Triggering Receptor 3/genetics
  • RNA, Viral/genetics
  • Sensitivity and Specificity
  • Statistics, Nonparametric
  • Virus Replication/genetics
  • Young Adult


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