Virus or TLR Agonists Induce TRAIL-Mediated Cytotoxic Activity of Plasmacytoid Dendritic Cells

Abstract

Among dendritic cells, plasmacytoid dendritic cells (PDC) represent a functionally distinct lineage. Regarding innate immunity, PDC secrete large amounts of type I IFN upon viral exposure or stimulation by microbial products such as unmethylated CpG-motif containing oligo-DNA due to their selective expression of TLR7 and TLR9. We asked whether they could acquire cytotoxic functions during the early phases of infection or after activation with TLR7 or TLR9 agonists. In the present study, we describe a human PDC cell line called GEN2.2, derived from leukemic PDC, that shares most of the phenotypic and functional features of normal PDC. We show that after contact with the influenza virus, GEN2.2, as well as normal PDC, acquires TRAIL and killer activity against TRAIL-sensitive target cells. Moreover, we show that activation of GEN2.2 cells by CpG-motif containing oligo-DNA or R848 also induces TRAIL and endows them with the ability to kill melanoma cells. Therefore, PDC may represent a major component of innate immunity that could participate to the clearance of infected cells and tumor cells. This phenomenon could be relevant for the efficacy of TLR7 or TLR9 agonists in the therapy of infectious disease and cancer.

The Calcineurin B Subunit (CnB) Is a New Ligand of Integrin αM That Mediates CnB-Induced Apo2L/TRAIL Expression in Macrophages

“…TRAIL induces apoptosis of a variety of tumor cells while displaying no cytotoxicity against most normal cells; this makes it a promising new agent for cancer therapy. It has been reported that in immune cells, TRAIL is induced mainly by the type I or II IFN-mediated JAK/STAT (37)(38)(39)(40) and TLR agonist-mediated TLR pathways (41)(42)(43). To our knowledge, this is the first report that TRAIL expression is mediated by integrin aM, and our findings should add to understanding of the mechanisms regulating TRAIL expression.…”

“…It is expressed on activated T cells, NK cells, macrophages, monocytes, dendritic cells, and neutrophils and plays important roles in tumor surveillance and defense against viral infections and many other physiological and pathological processes (35,36). In immune cells, TRAIL is induced by several pathways including the type I or II IFN-mediated JAK/STAT (37)(38)(39)(40) and TLR agonist-mediated TLR pathways (41)(42)(43). Histone deacetylase inhibitors induce TRAIL in human breast tumors via the transcription factor Sp1 (44), and proline oxidase promotes TRAIL expression via NFAT (45).…”

Recurrent genomic aberrations combined with deletions of various tumour suppressor genes may deregulate the G1/S transition in CD4+CD56+ haematodermic neoplasms and contribute to the aggressiveness of the disease

“…In one case, DNA was obtained from a CD4+ CD56+ cell line (GEN2.2). 10 In the interests of clarity, the GEN2.2 line is referred to as case 1 throughout the manuscript.…”

Trafficking properties of plasmacytoid dendritic cells in health and disease

“…Finally, inflammatory chemokines can attract activated T cells to sites of inflammation [20]. Interestingly, it has been shown that PDCs can induce apoptosis of tumour and virus-infected cell lines, either directly by secreting TRAIL (TNF-related apoptosis-inducing ligand) upon activation, or indirectly via the effect of type I IFN on other cytotoxic cells [24,25]. PDCs contain abundant granzyme B, but the role of this enzyme as a cytotoxic molecule remains elusive, because PDCs, in contrast to other cytotoxic cells, lack the pore-forming perforin [1,26].…”