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ABSTRACT: The transcriptional regulator NGFI-A binding protein 2 (NAB2) and the early growth response (EGR) genes are key regulators of effector molecules, such as cell death-inducing genes. We have previously shown that NAB2 modulates the levels of expression of the Tumor Necrosis Factor (TNF) family member TNF-related apoptosis inducing ligand (TRAIL) in T cells and plasmacytoid DCs. Provided that TRAIL plays a key role in NK cell cytotoxicity towards infected and tumor cells, we investigated whether NAB2 also mediates TRAIL expression in human NK cells, and if so through which mechanisms. We show that NAB2 is induced in NK cells upon IL-2 and IL-15 stimulation, and promotes the induction of TRAIL. In addition, we show that the transcription factor EGR-1, which is upregulated by the same stimuli as NAB2, rather acts as a brake on TRAIL expression in NK cells. Overall, these data provide new mechanistic insights in the regulation of TRAIL, and show that the gene regulation through the NAB2/EGR axis allows for a highly controlled expression pattern of this effector molecule in NK cells.
Immunology letters 02/2013; · 2.91 Impact Factor
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ABSTRACT: Plasmacytoid dendritic cells (pDCs) not only play a crucial role during innate immunity by secreting bulk amounts of type I Interferons (IFNs) in response to Toll-like-receptor (TLR)-mediated pathogen recognition, but can also contribute to adaptive immunity by activation of antigen-specific T cells. Furthermore, it is well-established that pDCs contribute to the pathogenesis of autoimmune diseases, including lupus. IL-21 is a cytokine produced by activated CD4(+) T and NKT cells and has a pleiotropic role in immunity by controlling myeloid DC, NK(T), T and B cell functions. It has remained elusive whether IL-21 affects pDCs. Here we investigated the role of IL-21 in human pDC activation and function and observed that IL-21 activated STAT3 in line with the finding that pDCs express the IL-21 receptor. While IL-21 did not affect TLR-induced type I IFNs, IL-6 and TNF-α nor expression of major-histocompatibilty-complex-class-II (MHC-II) or co-stimulatory molecules, IL-21 markedly increased expression of the serine protease Granzyme B (GrB). We demonstrate that GrB induction was in part responsible for IL-21-mediated downmodulation of CD4(+) T cell proliferation induced by TLR pre-activated pDCs. Collectively, our data provide evidence that pDCs are important cells to consider when investigating the role of IL-21 in immunity or pathogenesis.
Blood 02/2013; · 9.90 Impact Factor
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ABSTRACT: Plasmacytoid dendritic cells (pDCs) are key players in antiviral immunity. In addition to massive type I interferon production, activated pDCs express the apoptosis-inducing molecule TRAIL, which enables them to clear infected cells that express the TRAIL receptors TRAIL-R1 and TRAIL-R2. In this study, we examined the molecular mechanisms that govern TRAIL expression in human pDCs. We identify NGFI-A-binding protein 2 (NAB2) as a novel transcriptional regulator that governs TRAIL induction in stimulated pDCs. We show with the pDC-like cell line CAL-1 that NAB2 is exclusively induced downstream of TLR7 and TLR9 signaling, and not upon type I IFN-R signaling. Furthermore, PI3K signaling is required for NAB2-mediated TRAIL expression. Finally, we show that TRAIL induction in CpG-activated human pDCs occurs through two independent signaling pathways: the first is initiated through TLR9 signaling upon recognition of nucleic acids, followed by type I IFN-R-mediated signaling. In conclusion, our data suggest that these two pathways are downstream of different activation signals, but act in concert to allow for full TRAIL expression in pDCs.
European Journal of Immunology 07/2012; · 5.10 Impact Factor
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Julien J Karrich, Melania Balzarolo,
Heike Schmidlin,
Marion Libouban,
Maho Nagasawa,
Rebecca Gentek,
Shimeru Kamihira,
Takahiro Maeda,
Derk Amsen,
Monika C Wolkers,
Bianca Blom
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ABSTRACT: Plasmacytoid dendritic cells (pDCs) selectively express Toll-like receptor (TLR)-7 and TLR-9, which allow them to rapidly secrete massive amounts of type I interferons after sensing nucleic acids derived from viruses or bacteria. It is not completely understood how development and function of pDCs are controlled at the transcriptional level. One of the main factors driving pDC development is the ETS factor Spi-B, but little is known about its target genes. Here we demonstrate that Spi-B is crucial for the differentiation of hematopoietic progenitor cells into pDCs by controlling survival of pDCs and its progenitors. In search for Spi-B target genes, we identified the antiapoptotic gene Bcl2-A1 as a specific and direct target gene, thereby consolidating the critical role of Spi-B in cell survival.
Blood 04/2012; 119(22):5191-200. · 9.90 Impact Factor
