HCV glycoprotein E2 is a novel BDCA-2 ligand and acts as an inhibitor of IFN production by plasmacytoid dendritic cells.
The elimination of hepatitis C virus (HCV) in > 50% of chronically infected patients by treatment with IFN-α suggests that plasmacytoid dendritic cells (pDCs), major producers of IFN-α, play an important role in the control of HCV infection. However, despite large amounts of Toll-like receptor 7-mediated IFN-α, produced by pDCs exposed to HCV-infected hepatocytes, HCV still replicates in infected liver. Here we show that HCV envelope glycoprotein E2 is a novel ligand of pDC C-type lectin immunoreceptors (CLRs), blood DC antigen 2 (BDCA-2) and DC-immunoreceptor (DCIR). HCV particles inhibit, via binding of E2 glycoprotein to CLRs, production of IFN-α and IFN-λ in pDCs exposed to HCV-infected hepatocytes, and induce in pDCs a rapid phosphorylation of Akt and Erk1/2, in a manner similar to the crosslinking of BDCA-2 or DCIR. Blocking of BDCA-2 and DCIR with Fab fragments of monoclonal antibodies preserves the capacity of pDCs to produce type I and III IFNs in the presence of HCV particles. Thus, negative interference of CLR signaling triggered by cell-free HCV particles with Toll-like receptor signaling triggered by cell-associated HCV results in the inhibition of the principal pDC function, production of IFN.
INSERM/Unité Mixte de Recherche (UMR) 1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
Jonathan
J
Florentin
Besma
B
Aouar
Clélia
C
Dental
Christine
C
Thumann
Guylène
G
Firaguay
Francoise
F
Gondois-Rey
Vassili
V
Soumelis
Thomas F
TF
Baumert
Jacques A
JA
Nunès
Daniel
D
Olive
Ivan
I
Hirsch
Ruzena
R
Stranska
D000818:Animals; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D016174:Hepacivirus / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007372:Interferons / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000821:virology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000276:immunology* / Q000378:metabolism
C423004:CLEC4A protein, human; C443299:CLEC4C protein, human; D037181:Lectins, C-Type; D008024:Ligands; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D051199:Toll-Like Receptor 7; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; D007372:Interferons; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases