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Natural killer p46 High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis
Author(s) -
Krämer Benjamin,
Körner Christian,
Kebschull Moritz,
Glässner Andreas,
Eisenhardt Marianne,
Nischalke HansDieter,
Alexander Michael,
Sauerbruch Tilman,
Spengler Ulrich,
Nattermann Jacob
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25804
Subject(s) - biology , interleukin 21 , cytolysis , interleukin 12 , lymphokine activated killer cell , natural killer cell , immunology , cell , flow cytometry , hepatitis c virus , cytotoxic t cell , cancer research , t cell , virus , immune system , in vitro , genetics , biochemistry
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. (H EPATOLOGY 2012)