Amy Stone presenting:
HCV glycoprotein E2 is a novel BDCA-2 ligand and acts as an inhibitor of IFN production by plasmacytoid dendritic cells.
Florentin J, Aouar B, Dental C, Thumann C, Firaguay G, Gondois-Rey F, Soumelis V, Baumert TF, Nunès JA, Olive D, Hirsch I, Stranska R.
Institut National de la Sante et de la Recherche Medicale (Inserm) U 1068, Centre de Recherche en Cancerologie de Marseille (CRCM), Marseille, France;
The elimination of hepatitis C virus (HCV) in more than 50% of chronically infected patients by treatment with interferon-α (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 (TLR7)-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 cross-linking 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 TLR signaling triggered by cell-associated HCV results in inhibition of the principal pDC function - production of IFN.