HCV glycoprotein E2 is a novel BDCA-2 ligand and acts as an inhibitor of IFN production by plasmacytoid dendritic cells

Abstract

IntroductionThe eradication of hepatitis C virus (HCV) in Ͼ 50% of chronically infected patients by treatment with IFN-␣ 1,2 suggests that production of endogenous IFN-␣ plays an important role in the control of HCV infection. Plasmacytoid dendritic cells (pDCs) are a highly specialized subset of dendritic cells that function as sentinels for viral infection and are responsible for production of type I (IFN-␣ and ␤) and type III (IFN-/IL-28/29) IFNs, proinflammatory cytokines, and antigen presentation during viral infection. [3][4][5][6] pDCs are able to detect genetic material of viruses with a subset of Toll-like receptors (TLRs) localized to the endosomal compartment. 7 These nucleotide-sensing TLRs include TLR7, which recognizes single-stranded RNA, and TLR9, which recognizes DNA.In addition to nucleotide-sensing TLRs, pDCs also recognize pathogens through a battery of cell surface regulatory receptors, including Fc (FcR) and C-type lectin receptors (CLRs). The principal function of these regulatory receptors on pDCs is to facilitate antigen capture and to prevent aberrant immune responses by modulating production of type I IFNs and proinflammatory cytokines. 7 Some of these receptors, such as a member of CLR family, blood DC antigen 2 (BDCA-2), associate with the ␥-chain of Fc⑀RI receptor, which contains an immunoreceptor tyrosinebased activation motif. In pDCs, triggering of these receptors initiates a signaling pathway similar to the one that occurs downstream of the B-cell receptor. 8 Other CLRs of pDC, such as DC-immunoreceptor (DCIR), 9 contain an immunoreceptor tyrosinebased inhibitory motif. Triggering of BDCA-2 8,10 or DCIR 9 inhibits TLR9-and in some cases TLR7-induced production of type I IFNs and proinflammatory cytokines.Several reports have shown that exposure of pDCs from healthy donors to HCV particles results in no or only weak production of type I IFN. [11][12][13][14][15] However, in addition to this passive role, HCV particles also actively impair production of IFN-␣ triggered in pDCs by synthetic agonists of TLR9. 11,13 In contrast to HCV particles, a recent report has shown that HCV-infected hepatoma cells induce in pDCs a robust TLR7-mediated production of type I IFN. 14 Here we investigated whether HCV particles suppress production of IFN-␣ induced in pDCs by HCV-infected hepatoma cells. Furthermore, we investigated the mechanism of the impairment of pDC functions by HCV particles. We demonstrate that, in addition to type I IFNs, exposure of pDCs to HCV-infected hepatoma cells resulted in the production of type III IFNs and that HCV particles or HCV envelope glycoprotein E2 inhibited the production of both types of IFNs by binding to CLRs, BDCA-2 and DCIR. We further show that HCV particles 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 mAbs protects pDCs against the inhibition of IFN production induced by HCV particles. Thus, negative interference of CLR signaling t...

The Plasmacytoid Dendritic Cell as the Swiss Army Knife of the Immune System: Molecular Regulation of Its Multifaceted Functions

“…Viruses can highjack the signaling pathways downstream of such receptors and escape from immune recognition (Figure 2). For example, the hepatitis C virus (HCV) envelope glycoprotein E2 binds to BDCA2 and DCIR, which inhibits IFNα production in pDC when exposed to HCV-infected hepatocytes(23). Moreover, exposure of pDC to HCV-infected hepatoma cells prevents NFκB phosphorylation via an endocytosis-dependent mechanism resulting in a lack of cell surface expression of CD40, CCR7, CD86 and TRAIL, and of TNFα and IL6 secretion(24).…”

The plasmacytoid dendritic cell: at the cross-roads in asthma

“…Similarly, activation of either human BDCA-2 or murine Siglec H induces an inhibitory signal through spleen tyrosine kinase (Syk) to attenuate IFN-I production [81]. A recent report found that hepatitis C viral glycoprotein e2 ligates BDCA-2 to inhibit pDC production of IFN-I and III [82], while elevated phosphorylation of Syk is associated with attenuated IFN-I production by HIV-stimulated pDCs [83]. It will be important to determine whether respiratory viruses, and in particular those associated with the onset of asthma, are able to engage BDCA-2 or ILT7 to evoke inhibitory signals that suppress IFN-I release.…”

Future considerations for dendritic cell immunotherapy against chronic viral infections

“…In addition, pDCs were reported to not express the cell surface proteins CD40, CD86, CCR7 and TRAIL [64]. HCV E2 protein can bind pDC-specific type II C-type lectin (BDCA) and DC immunoreceptor (DCIR) and inhibit TLR7 and TLR9-mediated IFN-a or IFN-l release by pDCs [65]. Furthermore, mDCs of CHC patients show elevated expression of Fas ligand and PD-L2 compared with those from healthy controls, and have cytotoxic effects on both autologous and heterologous T cells.…”