Jeroen den Dunnen
VU University Medical Center
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Publication
Featured researches published by Jeroen den Dunnen.
Nature Immunology | 2009
Sonja I. Gringhuis; Jeroen den Dunnen; Manja Litjens; Michiel van der Vlist; Teunis B. H. Geijtenbeek
Cooperation between different innate signaling pathways induced by pattern-recognition receptors (PRRs) on dendritic cells (DCs) is crucial for tailoring adaptive immunity to pathogens. Here we show that carbohydrate-specific signaling through the C-type lectin DC-SIGN tailored cytokine production in response to distinct pathogens. DC-SIGN was constitutively associated with a signalosome complex consisting of the scaffold proteins LSP1, KSR1 and CNK and the kinase Raf-1. Mannose-expressing Mycobacterium tuberculosis and human immunodeficiency virus type 1 (HIV-1) induced the recruitment of effector proteins to the DC-SIGN signalosome to activate Raf-1, whereas fucose-expressing pathogens such as Helicobacter pylori actively dissociated the KSR1–CNK–Raf-1 complex from the DC-SIGN signalosome. This dynamic regulation of the signalosome by mannose- and fucose-expressing pathogens led to the enhancement or suppression of proinflammatory responses, respectively. Our study reveals another level of plasticity in tailoring adaptive immunity to pathogens.
Nature Immunology | 2010
Sonja I. Gringhuis; Michiel van der Vlist; Linda M van den Berg; Jeroen den Dunnen; Manja Litjens; Teunis B. H. Geijtenbeek
Pattern-recognition receptors (PRRs) elicit antiviral immune responses to human immunodeficiency virus type 1 (HIV-1). Here we show that HIV-1 required signaling by the PRRs Toll-like receptor 8 (TLR8) and DC-SIGN for replication in dendritic cells (DCs). HIV-1 activated the transcription factor NF-κB through TLR8 to initiate the transcription of integrated provirus by RNA polymerase II (RNAPII). However, DC-SIGN signaling was required for the generation of full-length viral transcripts. Binding of the HIV-1 envelope glycoprotein gp120 to DC-SIGN induced kinase Raf-1–dependent phosphorylation of the NF-κB subunit p65 at Ser276, which recruited the transcription-elongation factor pTEF-b to nascent transcripts. Transcription elongation and generation of full-length viral transcripts was dependent on pTEF-b-mediated phosphorylation of RNAPII at Ser2. Inhibition of either pathway abrogated replication and prevented HIV-1 transmission. Thus, HIV-1 subverts crucial components of the immune system for replication that might be targeted to prevent infection and dissemination.
PLOS Pathogens | 2008
Joppe W. Hovius; Marein A. W. P. de Jong; Jeroen den Dunnen; Manja Litjens; Erol Fikrig; Tom van der Poll; Sonja I. Gringhuis; Teunis B. H. Geijtenbeek
Ixodes ticks are major vectors for human pathogens, such as Borrelia burgdorferi, the causative agent of Lyme disease. Tick saliva contains immunosuppressive molecules that facilitate tick feeding and B. burgdorferi infection. We here demonstrate, to our knowledge for the first time, that the Ixodes scapularis salivary protein Salp15 inhibits adaptive immune responses by suppressing human dendritic cell (DC) functions. Salp15 inhibits both Toll-like receptor- and B. burgdorferi–induced production of pro-inflammatory cytokines by DCs and DC-induced T cell activation. Salp15 interacts with DC-SIGN on DCs, which results in activation of the serine/threonine kinase Raf-1. Strikingly, Raf-1 activation by Salp15 leads to mitogen-activated protein kinase kinase (MEK)-dependent decrease of IL-6 and TNF-α mRNA stability and impaired nucleosome remodeling at the IL-12p35 promoter. These data demonstrate that Salp15 binding to DC-SIGN triggers a novel Raf-1/MEK-dependent signaling pathway acting at both cytokine transcriptional and post-transcriptional level to modulate Toll-like receptor–induced DC activation, which might be instrumental to tick feeding and B. burgdorferi infection, and an important factor in the pathogenesis of Lyme disease. Insight into the molecular mechanism of immunosuppression by tick salivary proteins might provide innovative strategies to combat Lyme disease and could lead to the development of novel anti-inflammatory or immunosuppressive agents.
Cancer Immunology, Immunotherapy | 2009
Jeroen den Dunnen; Sonja I. Gringhuis; Teunis B. H. Geijtenbeek
Effective immune responses depend on the recognition of pathogens by dendritic cells (DCs) through pattern recognition receptors (PRRs). These receptors induce specific signaling pathways that lead to the induction of immune responses against the pathogens. It is becoming evident that C-type lectins are also important PRRs. In particular, the C-type lectin DC-SIGN has emerged as a key player in the induction of immune responses against numerous pathogens by modulating TLR-induced activation. Recent reports have begun to elucidate the molecular mechanisms underlying these immune responses. Upon pathogen binding, DC-SIGN induces an intracellular signaling pathway with a central role for the serine/threonine kinase Raf-1. For several pathogens that interact with DC-SIGN, including Mycobacterium tuberculosis and HIV-1, Raf-1 activation leads to acetylation of NF-κB subunit p65, which induces specific gene transcription profiles. In addition, other DC-SIGN-ligands induce different signaling pathways downstream of Raf-1, indicating that DC-SIGN-signaling is tailored to the pathogen. In this review we will discuss in detail the current knowledge about DC-SIGN signaling and its implications on immunity.
Methods of Molecular Biology | 2009
Lot de Witte; Marein A.W.P. de Jong; Jeroen den Dunnen; Yvette van Kooyk; Teunis B. H. Geijtenbeek
Dendritic cells (DCs) are crucial in the defence against invading pathogens. These professional antigen-presenting cells express a diversity of pattern recognition receptors to recognize pathogens and to induce adaptive immune responses. However, pathogens have also developed several mechanisms to suppress or modulate DC function through specific receptors, thereby ensuring pathogen survival and dissemination. In this chapter, we will discuss techniques to identify and functionally characterize pathogen receptors on DCs and to determine whether DCs elicit protective immune responses or whether pathogens subvert these responses to escape immunity.
Immunity | 2007
Sonja I. Gringhuis; Jeroen den Dunnen; Manja Litjens; Bert van het Hof; Yvette van Kooyk; Teunis B. H. Geijtenbeek
Current Opinion in Immunology | 2007
Sandra J. van Vliet; Jeroen den Dunnen; Sonja I. Gringhuis; Teunis B. H. Geijtenbeek; Yvette van Kooyk
Microbes and Infection | 2007
Catharina W. Wieland; Estella A. Koppel; Jeroen den Dunnen; Sandrine Florquin; Andrew N. J. McKenzie; Yvette van Kooyk; Tom van der Poll; Teunis B. H. Geijtenbeek
European Journal of Oral Sciences | 2009
Teunis B. H. Geijtenbeek; Jeroen den Dunnen; Sonja I. Gringhuis
Archive | 2009
Teunis B. H. Geijtenbeek; Jeroen den Dunnen; Sonja I. Gringhuis