Free HTLV-1 induces TLR7-dependent innate immune response and TRAIL relocalization in killer plasmacytoid dendritic cells

Abstract

A recent report demonstrated that free human T-cell leukemia virus 1 (HTLV-1) could infect plasmacytoid dendritic cells (pDCs). The major role of pDCs is to secrete massive levels of interferon-␣ (IFN-␣) upon virus exposure; however, the induction of IFN-␣ by HTLV-1 remains unknown. We demonstrate here that cellfree HTLV-1 generated a pDC innate immune response by producing massive levels of IFN-␣ that were inhibited by anti-HTLV-1 antibodies. HTLV-1 induced costimulatory molecules and rapid expression of the apoptotic ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Furthermore, HTLV-1 stimulated pDC-induced apoptosis of CD4 ؉ T cells expressing DR5, transforming pDCs into IFN-producing killer pDCs. We also observed that an endosomal acidification inhibitor and a Toll-like receptor-7 (TLR7)-specific blocker drastically inhibited pDC response to HTLV-1. Three-dimensional microscopy analysis revealed that unstimulated pDCs were "dormant" IFNproducing killer pDCs with high levels of intracellular TRAIL that could be rapidly mobilized to the surface in response to TLR7 activation. Inhibition of viral degradation in endosomes by chloroquine maintained viral integrity, allowing virus detection by 3-dimensional microscopy. We demonstrate that pDCs respond to cell-free HTLV-1 by producing high levels of IFN-␣ and by mobilizing TRAIL on cell surface after TLR7 triggering. This is the first demonstration of an innate immune response induced by free HTLV-1. (Blood. 2010;115:2177-2185) IntroductionHuman T-cell leukemia virus 1 (HTLV-1), the first characterized human retrovirus, 1 has been identified as the causative agent for adult T-cell leukemia/lymphoma (ATLL) 2,3 and HTLV-1-associated myelopathy/tropical spastic paraparesis, 4 uveitis, and infective dermatitis in children. 5 HTLV-1 virions infect CD4 ϩ T cells, which represent the main target for HTLV-1 infection in peripheral blood. HTLV-1-associated diseases occur after long periods of virus latency. 6 For years it has been thought that unlike other retroviruses, free virions were poorly infectious. 7 However, Jones et al 8 recently reported that freshly isolated myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) are efficiently and productively infected by cell-free HTLV-1. Furthermore, infected mDCs and pDCs were able to transfer virions to autologous CD4 ϩ T cells, clearly demonstrating that cell-free HTLV-1 can be infectious and target DCs. 8 pDCs participate in innate and adaptive immunity, 9,10 are located in blood and lymphoid organs, 10,11 and produce up to 1000-fold more interferon-␣ (IFN-␣) than other cell types in response to virus exposure. 12 Three molecules have been characterized for HTLV-1 entry into cells, heparan sulfate proteoglycans 13 and BDCA-4 (also called neuropilin-1) 14 for the initial virus binding to target cells 15 and glucose transporter 1 for the postattachment and the viral fusion. 16,17 Interestingly, BDCA-4 is expressed by mDC and T cells 18,19 but cells expressing the greatest level of BDCA...

TRAIL+ Human Plasmacytoid Dendritic Cells Kill Tumor Cells In Vitro: Mechanisms of Imiquimod- and IFN-α–Mediated Antitumor Reactivity

“…The finding that DCs can express cytotoxic molecules after TLR7/8 and TLR9 stimulation (8,10) and can use them to effectively lyse cancer cells (9,15,23) as well as virus-infected targets (12) adds a novel facet to our current concept of DC biology. In this study, we sought to unravel the molecular events governing pDC cytotoxicity and, thus, gain a better understanding of the potential role of cytotoxic DCs in health and disease.…”

“…HIV, human T cell leukemia virus-1, and influenza virus, all natural ligands of TLR7, trigger a pDC innate immune response that not only involves the massive production of IFN-a, but also the upregulation of functionally active TRAIL (TRAIL/ Apo-2L/TNFSF10) (8)(9)(10). TRAIL is also expressed by HIVinfected pDCs (8,11,12), and, notably, TRAIL + pDCs may kill CD4 + T cells isolated from HIV-infected patients (12) and thus perhaps contribute to T cell depletion during HIV viremia.…”

Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells

“…Several studies have demonstrated that IFNs are able to induce apoptosis on malignant cells, either by directly exerting cytotoxic effects or by enhancing the expression of death-inducing molecules, such as TNF-related apoptosisinducing ligand (TRAIL) and FasL (12)(13)(14). Notably, human pDCs were reported to express TRAIL and FasL or to release granzyme B upon TLR7/8 stimulation by viruses or synthetic ligands (15)(16)(17). We and others have shown that topical application of Imi induces epidermal thickening and dermal inflammation with infiltration of immune cells and production of IFN-α and TNF-α (18,19).…”

Innate Sensing of Foamy Viruses by Human Hematopoietic Cells

“…However, when resistance to infection is circumvented, HIV-1 induces DC maturation and type I IFN production (44). HTLV-1 is also sensed by pDCs in culture experiments (11). In vivo, some murine retroviruses (MMTV and MLV), triggers immune activation through TLR7, as demonstrated using TLR7-KO mice (33).…”