title: Altered functions of plasmacytoid dendritic cells and reduced cytolytic activity of natural killer cells in patients with chronic HBV infection.
abstract: OBJECTIVE
  Hepatitis B virus (HBV) modulates the immune system to escape clearance. Plasmacytoid dendritic cells (pDCs) initiate antiviral immunity and might determine outcomes of HBV infections. Functional defects in pDCs and natural killer (NK) cells have been reported in patients with chronic HBV infection. However, the mechanisms of these immune dysfunctions and the interactions between pDCs and NK cells have not been determined. We investigated features of pDCs from patients with chronic HBV infection and their interactions with NK cells.
  
  
  METHODS
  We used flow cytometry and cytokine assays to analyze pDCs from patients with chronic HBV infection (118 aviremic and 67 viremic) and compared them with pDCs from uninfected individuals (controls). We performed coculture assays to analyze the ability of pDCs to activate heterologous NK cells.
  
  
  RESULTS
  Circulating and hepatic pDCs from patients with chronic HBV infection had higher levels of activation than pDCs from controls and defective responses to stimulation with Toll-like receptor 9 ligand (TLR9-L), regardless of the patient's viral load. TLR9-L-activated pDCs from viremic patients with HBV did not induce cytolytic activity of NK cells. This altered function of pDCs was associated with reduced expression of OX40L and could be reproduced by incubating control pDCs with plasma from viremic patients with HBV. A high level of interferon-induced protein 10 (IP-10 or CXCL10) and hepatitis B surface and e antigens might induce these defective pDC functions.
  
  
  CONCLUSIONS
  HBV escapes antiviral immunity by altering pDC functions, to disrupt interactions between pDC and NK cells. This could reduce immune control of HBV and lead to chronic infection.
authors.affiliation: R&D Laboratory, EFS Rhone-Alpes, La Tronche, France.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Martinet
authors.forename: Tania
authors.initials: T
authors.lastname: Dufeu-Duchesne
authors.forename: Juliana
authors.initials: J
authors.lastname: Bruder Costa
authors.forename: Sylvie
authors.initials: S
authors.lastname: Larrat
authors.forename: Alice
authors.initials: A
authors.lastname: Marlu
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroy
authors.forename: Joel
authors.initials: J
authors.lastname: Plumas
authors.forename: Caroline
authors.initials: C
authors.lastname: Aspord
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002450:Cell Communication / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000097:blood; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000473:pathology / Q000502:physiology*; D005260:Female; D006515:Hepatitis B virus / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D016898:Interferon-alpha / Q000378:metabolism; D007694:Killer Cells, Natural / Q000473:pathology / Q000502:physiology*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D053278:OX40 Ligand / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000502:physiology; D019562:Viral Load / Q000502:physiology
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D016898:Interferon-alpha; D008024:Ligands; D053278:OX40 Ligand; C495371:TLR9 protein, human; C089251:TNFSF4 protein, human; D051217:Toll-Like Receptor 9