title: Interferon α-stimulated natural killer cells from patients with acute hepatitis C virus (HCV) infection recognize HCV-infected and uninfected hepatoma cells via DNAX accessory molecule-1.
abstract: BACKGROUND
  Natural killer (NK) cells are an important component of the innate immune defense against viruses, including hepatitis C virus (HCV). The cell culture system using HCV-permissive Huh-7.5 cells make studies on interaction of NK cells and HCV-infected target cells possible. We used this system to characterize interactions of HCV-infected Huh-7.5 cells and NK cells from healthy controls and patients with acute HCV infection.
  
  
  METHODS
  IFNα- and IL-2 stimulated NK cells were cultured with HCV-infected hepatoma cells and subsequently analyzed (for degranulation and cytokine production) via multicolour flow cytometry. Luciferase assyas have been used to study inhibition of HCV replication. Further, PBMC from patients with acute hepatitis C as well as HCV-infected Huh7.5 cells have been analyzed via flow cytometry for expression of NK cell receptors and ligands, respectively.
  
  
  RESULTS
  After interferon (IFN) α stimulation, NK cells from healthy controls and patients with acute hepatitis C efficiently recognized both HCV-infected and uninfected hepatoma cells. Subsequent dissection of receptor-ligand interaction revealed a dominant role for DNAM-1 and a complementary contribution of NKG2D for NK cell activation in this setting. Furthermore, IFN-α-stimulated NK cells effectively inhibited HCV replication in a DNAM-1-dependent manner.
  
  
  CONCLUSIONS
  Human NK cells recognize HCV-infected hepatoma cells after IFN-α stimulation in a DNAM-1-dependent manner. Furthermore, interaction of IFN-α-stimulated NK cells with HCV-infected hepatoma cells efficiently reduced HCV replication. This study opens up future studies of NK cell interaction with HCV-infected hepatocytes to gain further insight into the pathogenesis of human HCV infection and the therapeutic effects of IFN-α.
authors.affiliation: Department for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.
authors.forename: Kerstin A
authors.initials: KA
authors.lastname: Stegmann
authors.forename: Niklas K
authors.initials: NK
authors.lastname: Björkström
authors.forename: Sandra
authors.initials: S
authors.lastname: Ciesek
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lunemann
authors.forename: Jerzy
authors.initials: J
authors.lastname: Jaroszewicz
authors.forename: Johannes
authors.initials: J
authors.lastname: Wiegand
authors.forename: Phillipp
authors.initials: P
authors.lastname: Malinski
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Dustin
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
authors.forename: Markus
authors.initials: M
authors.lastname: Cornberg
authors.forename: Hans-Gustaf
authors.initials: HG
authors.lastname: Ljunggren
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
mesh_terms: D000208:Acute Disease; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D000998:Antiviral Agents / Q000627:therapeutic use*; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D006526:Hepatitis C / Q000276:immunology / Q000473:pathology*; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D055607:Receptors, Natural Killer Cell / Q000378:metabolism; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000998:Antiviral Agents; D000098862:T Lineage-Specific Activation Antigen 1; D016898:Interferon-alpha; D007376:Interleukin-2; D055607:Receptors, Natural Killer Cell