Teunis B H Geijtenbeek

University of Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (148)1064.39 Total impact

  • Joris K Sprokholt · Nina Hertoghs · Teunis B H Geijtenbeek
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    ABSTRACT: In this chapter we describe a fluorescent bead-binding assay, which is an efficient and feasible method to measure interaction between ligands and receptors on cells. In principle, any ligand can be coated on fluorescent beads either directly or via antibodies. Binding between ligand-coated beads and cells can be measured by flow cytometry, which results in an easily quantifiable readout. Furthermore, it allows measuring of binding by specific cell subsets within a mixed cell population. Overall, this method is a convenient and easily standardized assay for measuring binding.
    No preview · Article · Jan 2016 · Methods in molecular biology (Clifton, N.J.)
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    ABSTRACT: HIV-1 exploits the cellular machinery for replication and therefore several interactions with cellular factors take place, some of which are yet unknown. We identified GTPase-activating protein-(SH3 domain)-binding protein 1 (G3BP1) as a cellular factor that restricts HIV-1, by analyzing transcriptome profiles of in vitro-cytokine-activated macrophages that are non-permissive to HIV-1 replication. Silencing of G3BP1 by RNA interference resulted in increased HIV-1 replication in primary T-cells and macrophages, but did not affect replication of other retroviruses. G3BP1 specifically interacted with HIV-1 RNA in the cytoplasm, suggesting that it sequesters viral transcripts, thus preventing translation or packaging. G3BP1 was highly expressed in resting naïve or memory T-cells from healthy donors and HIV-1 infected patients, but significantly lower in IL-2-activated T-cells. These results strongly suggest that G3BP1 captures HIV-1 RNA transcripts and thereby restricts mRNA translation, viral protein production and virus particle formation.
    No preview · Article · Dec 2015 · Virology
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    ABSTRACT: Human epidermal and mucosal Langerhans cells (LCs) express the C-type lectin receptor langerin that functions as a pattern recognition receptor. LCs are among the first immune cells to interact with HIV-1 during sexual transmission. In this study, we demonstrate that langerin not only functions as a pattern recognition receptor but also as an adhesion receptor mediating clustering between LCs and dendritic cells (DCs). Langerin recognized hyaluronic acid on DCs and removal of these carbohydrate structures partially abrogated LC-DC clustering. Because LCs did not cross-present HIV-1-derived Ags to CD8(+) T cells in a cross-presentation model, we investigated whether LCs were able to transfer Ags to DCs. LC-DC clustering led to maturation of DCs and facilitated Ag transfer of HIV-1 to DCs, which subsequently induced activation of CD8(+) cells. The rapid transfer of Ags to DCs, in contrast to productive infection of LCs, suggests that this might be an important mechanism for induction of anti-HIV-1 CD8(+) T cells. Induction of the enzyme hyaluronidase-2 by DC maturation allowed degradation of hyaluronic acid and abrogated LC-DC interactions. Thus, we have identified an important function of langerin in mediating LC-DC clustering, which allows Ag transfer to induce CTL responses to HIV-1. Furthermore, we showed this interaction is mediated by hyaluronidase-2 upregulation after DC maturation. These data underscore the importance of LCs and DCs in orchestrating adaptive immunity to HIV-1. Novel strategies might be developed to harness this mechanism for vaccination.
    Full-text · Article · Aug 2015 · The Journal of Immunology
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    ABSTRACT: A hallmark of HIV-1 infection is the lack of sterilizing immunity. Dendritic cells (DCs) are crucial in the induction of immunity, and lack of DC activation might underlie the absence of an effective anti-HIV-1 response. We have investigated how HIV-1 infection affects maturation of DCs. Our data show that even though DCs are productively infected by HIV-1, infection does not induce DC maturation. HIV-1 infection actively suppresses DC maturation, as HIV-1 infection inhibited TLR-induced maturation of DCs and thereby decreased the immune stimulatory capacity of DCs. Interfering with SAMHD1 restriction further increased infection of DCs, but did not lead to DC maturation. Notably, higher infection observed with SAMHD1 depletion correlated with a stronger suppression of maturation. Furthermore, blocking reverse transcription rescued TLR-induced maturation. These data strongly indicate that HIV-1 replication does not trigger immune activation in DCs, but that HIV-1 escapes immune surveillance by actively suppressing DC maturation independent of SAMHD1. Elucidation of the mechanism of suppression can lead to promising targets for therapy or vaccine design.
    No preview · Article · May 2015 · The Journal of Immunology
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    ABSTRACT: Traditional medicines that stimulate or modulate the immune system can be used as innovative approaches to treat immunological diseases. The herbal medicine IMOD has been shown to strongly modulate immune responses in several animal studies as well as in clinical trials. However, little is known about the mechanisms of IMOD to modulate immunity. Here we have investigated whether IMOD modulates the immunological function of human dendritic cells (DCs). IMOD alone did not induce DC maturation nor production of cytokines. Notably, IMOD decreased the production of pro-inflammatory cytokines IL-6, IL-12 p70, and TNFα by LPS-activated DCs at both mRNA and protein levels in a dose dependent manner. In contrast, treatment with IMOD did not affect LPS induced-production of the anti-inflammatory cytokine IL-10. Furthermore, IMOD inhibited T cell activation/proliferation by LPS-treated DCs and skewed T-cells responses toward the T helper type 2 polarization. These data strongly indicate that IMOD has a potent immunomodulatory ability that affects TLR signaling and thereby modulates DC function. Insight into the immunomodulatory effect of herbal medicine IMOD may provide innovative strategies to affect the immune system and to help combat various diseases.
    Full-text · Article · Mar 2015 · Frontiers in Pharmacology
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    ABSTRACT: Background Human Langerhans cells (LCs) reside in foreskin and vaginal mucosa and are the first immune cells to interact with HIV-1 during sexual transmission. LCs capture HIV-1 through the C-type lectin receptor langerin, which routes the virus into Birbeck granules (BGs), thereby preventing HIV-1 infection. BGs are langerin-positive organelles exclusively present in LCs, however, their origin and function are unknown.ResultsHere, we not only show that langerin and caveolin-1 co-localize at the cell membrane and in vesicles but also that BGs are langerin/caveolin-1-positive vesicles that are linked to the lysosomal degradation pathway in LCs. Moreover, inhibition of caveolar endocytosis in primary LCs abrogated HIV-1 sequestering into langerin+ caveolar structures. Notably, both inhibition of caveolar uptake and silencing of caveolar structure protein caveolin-1 resulted in increased HIV-1 integration and subsequent infection. In contrast, inhibition of clathrin-mediated endocytosis did not affect HIV-1 integration, even though HIV-1 uptake was decreased, suggesting that clathrin-mediated endocytosis is not involved in HIV-1 restriction in LCs.Conclusions Thus, our data strongly indicate that BGs belong to the caveolar endocytosis pathway and that caveolin-1 mediated HIV-1 uptake is an intrinsic restriction mechanism present in human LCs that prevents HIV-1 infection. Harnessing this particular internalization pathway has the potential to facilitate strategies to combat HIV-1 transmission.
    Full-text · Article · Dec 2014 · Retrovirology
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    ABSTRACT: Dendritic cells (DCs) orchestrate antibody-mediated responses to combat extracellular pathogens including parasites by initiating T helper cell differentiation. Here we demonstrate that carbohydrate-specific signalling by DC-SIGN drives follicular T helper cell (TFH) differentiation via IL-27 expression. Fucose, but not mannose, engagement of DC-SIGN results in activation of IKKε, which collaborates with type I IFNR signalling to induce formation and activation of transcription factor ISGF3. Notably, ISGF3 induces expression of IL-27 subunit p28, and subsequent IL-27 secreted by DC-SIGN-primed DCs is pivotal for the induction of Bcl-6(+)CXCR5(+)PD-1(hi)Foxp1(lo) TFH cells, IL-21 secretion by TFH cells and T-cell-dependent IgG production by B cells. Thus, we have identified an essential role for DC-SIGN-induced ISGF3 by fucose-based PAMPs in driving IL-27 and subsequent TFH polarization, which might be harnessed for vaccination design.
    No preview · Article · Oct 2014 · Nature Communications
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    ABSTRACT: The cytosolic sensor MDA5 is crucial for antiviral innate immune defense against various RNA viruses including measles virus; as such, many viruses have evolved strategies to antagonize the antiviral activity of MDA5. Here, we show that measles virus escapes MDA5 detection by targeting the phosphatases PP1α and PP1γ, which regulate MDA5 activity by removing an inhibitory phosphorylation mark. The V proteins of measles virus and the related paramyxovirus Nipah virus interact with PP1α/γ, preventing PP1-mediated dephosphorylation of MDA5 and thereby its activation. The PP1 interaction with the measles V protein is mediated by a conserved PP1-binding motif in the C-terminal region of the V protein. A recombinant measles virus expressing a mutant V protein deficient in PP1 binding is unable to antagonize MDA5 and is growth impaired due to its inability to suppress interferon induction. This identifies PP1 antagonism as a mechanism employed by paramyxoviruses for evading innate immune recognition.
    Preview · Article · Jul 2014 · Cell Host & Microbe
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    ABSTRACT: Dendritic cells (DCs) are targets of measles virus (MV) and play central roles in viral dissemination. However, DCs express the RIG-I-like receptors (RLRs) RIG-I and Mda5 that sense MV and induce type I interferon (IFN) production. Given the potency of this antiviral response, RLRs are tightly regulated at various steps, including dephosphorylation by PP1 phosphatases, which induces their activation. We demonstrate that MV suppresses RIG-I and Mda5 by activating the C-type lectin DC-SIGN and inducing signaling that prevents RLR dephosphorylation. MV binding to DC-SIGN leads to activation of the kinase Raf-1, which induces the association of PP1 inhibitor I-1 with GADD34-PP1 holoenzymes, thereby inhibiting phosphatase activity. Consequently, GADD34-PP1 holoenzymes are unable to dephosphorylate RIG-I and Mda5, hence suppressing type I IFN responses and enhancing MV replication. Blocking DC-SIGN signaling allows RLR activation and suppresses MV infection of DCs. Thus, MV subverts DC-SIGN to control RLR activation and escape antiviral responses.
    Preview · Article · Jul 2014 · Cell Host & Microbe
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    ABSTRACT: Carbohydrate-specific signalling through DC-SIGN provides dendritic cells with plasticity to tailor immunity to the nature of invading microbes. Here we demonstrate that recognition of fucose-expressing extracellular pathogens like Schistosoma mansoni and Helicobacter pylori by DC-SIGN favors T helper cell type-2 (TH2) responses via activation of atypical NF-κB family member Bcl3. Crosstalk between TLR and DC-SIGN signalling results in TLR-induced MK2-mediated phosphorylation of LSP1, associated with DC-SIGN, upon fucose binding. Subsequently, IKKε and CYLD are recruited to phosphorylated LSP1. IKKε activation is pivotal for suppression of CYLD deubiquitinase activity and subsequent nuclear translocation of ubiquitinated Bcl3. Bcl3 activation represses TLR-induced proinflammatory cytokine expression, while enhancing interleukin-10 (IL-10) and TH2-attracting chemokine expression, shifting TH differentiation from TH1 to TH2 polarization. Thus, DC-SIGN directs adaptive TH2 immunity to fucose-expressing pathogens via an IKKε-CYLD-dependent signalling pathway leading to Bcl3 activation, which might be targeted in vaccination strategies or to prevent aberrant inflammation and allergy.
    No preview · Article · May 2014 · Nature Communications
  • T. B. Geijtenbeek · S. I. Gringhuis

    No preview · Article · May 2014 · Mycoses
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    ABSTRACT: Recognition of fungal pathogens by C-type lectin receptor (CLR) dectin-1 on human dendritic cells is essential for triggering protective antifungal TH1 and TH17 immune responses. We show that Fonsecaea monophora, a causative agent of chromoblastomycosis, a chronic fungal skin infection, evades these antifungal responses by engaging CLR mincle and suppressing IL-12, which drives TH1 differentiation. Dectin-1 triggering by F. monophora activates transcription factor IRF1, which is crucial for IL12A transcription via nucleosome remodeling. However, simultaneous F. monophora binding to mincle induces an E3 ubiquitin ligase Mdm2-dependent degradation pathway, via Syk-CARD9-mediated PKB signaling, that leads to loss of nuclear IRF1 activity, hence blocking IL12A transcription. The absence of IL-12 leads to impaired TH1 responses and promotes TH2 polarization. Notably, mincle is similarly exploited by other chromoblastomycosis-associated fungi to redirect TH responses. Thus, mincle is a fungal receptor that can suppress antifungal immunity and, as such, is a potential therapeutic target.
    Full-text · Article · Apr 2014 · Cell host & microbe
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    ABSTRACT: Beta-glucans in temporary wound dressings have immuno-stimulatory capacities and have been shown to enhance wound healing in burn patients. Curdlan is a 1,3-linked bacterial/fungal derived beta-glucan that induces inflammatory responses via the C-type lectin receptor dectin-1 on dendritic cells (DCs). Here we investigated the effect of beta-glucan curdlan and the role of dectin-1 expressed by keratinocytes (KCs) in wound healing. Curdlan enhanced migration, proliferation and wound closure of human KCs in a dectin-1 dependent manner, both in vitro and ex vivo. Our data suggest that curdlan induces human KC proliferation and migration and could therefore be used in creams to enhance wound healing.
    Full-text · Article · Mar 2014 · Cellular Immunology
  • Lauren M K Mason · Christiaan C Veerman · Teunis B H Geijtenbeek · Joppe W R Hovius
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    ABSTRACT: Borrelia burgdorferi sensu lato, the causative agent of Lyme borreliosis, is inoculated into the skin during an Ixodes tick bite where it is recognised and captured by dendritic cells (DCs). However, considering the propensity of Borrelia to disseminate, it would appear that DCs fall short in mounting a robust immune response against it. Many aspects of the DC-driven immune response to Borrelia have been examined. Recently, components of tick saliva have been identified that sabotage DC responses and aid Borrelia infection. In this review, we summarise what is currently known about the immune response of DCs to Borrelia and explore the mechanisms by which Borrelia manages to circumvent this immune response, with or without the help of tick salivary proteins.
    No preview · Article · Dec 2013 · Trends in Parasitology
  • A.M.G. Van Der Aar · S.I. Gringhuis · T.B.H. Geijtenbeek
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    ABSTRACT: Innate immune cells such as dendritic cells (DCs), Langerhans cells (LCs), and macrophages are equipped with pattern recognition receptors that sense invading pathogens and activate immune responses. Recognition of the heavily glycosylated human immunodeficiency virus type-1 (HIV-1) envelope proteins by innate immune cells is mediated through membrane-bound C-type lectin receptors (CLRs) that interact with the carbohydrate structures. In addition, soluble lectin receptors present in tissue or blood can also bind to HIV-1 glycans. Capture of HIV-1 through CLRs is crucial for antigen presentation and induction of antiviral immunity. Strikingly, HIV-1 has evolved to exploit these innate receptors to facilitate infection as well as promote transmission to CD4+ T cells. The outcome of HIV-1-glycan recognition by the host is strongly dependent on the cell type and receptors involved. Identification of the molecular mechanisms and functional results of glycan-mediated recognition of HIV-1 is essential for a better understanding of HIV-1 pathogenesis and will lead to the development of novel antiviral strategies. Here, we discuss the current knowledge on recognition of HIV-1 through innate lectin receptors and the implications for viral replication, transmission, and immunity. © Springer Science+Business Media New York 2014. All rights are reserved.
    No preview · Article · Nov 2013
  • Teunis B H Geijtenbeek · Sonja I Gringhuis

    No preview · Article · Mar 2013 · Nature Immunology
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    ABSTRACT: Human skin contains two distinct dendritic cell (DC) subsets: (i)Langerhans cells (LCs), expressing Langerin but not DC-SIGN are predominantly localized in the epidermis; and (ii) dermal DCs, expressing DC-SIGN but not Langerin, are observed mainly in the dermis. It is not known whether localization in the epidermis provides cues for LC differentiation. Here we show that E-cadherin expressed by epidermal keratinocytes (KCs) is crucial for differentiation of LCs. Monocytes differentiated into LC-like cells in presence of IL-4, GM-CSF, and TGF-β1. However, these LC-like cells expressed not only Langerin but also DC-SIGN. Notably, co-culturing of these LC-like cells with KCs expressing E-cadherin or recombinant E-cadherin strongly decreased expression of DC-SIGN and further induced a phenotype similar to purified epidermal LCs. Moreover, pretreatment of LC-like cells with anti-E-cadherin-specific antibody completely abolished their Langerin expression, indicating the requirement of E-cadherin-E-cadherin interactions for the differentiation into Langerin+ cells. These findings suggest that E-cadherin expressed by KCs provide environmental cues that induce differentiation of LCs in the epidermis.
    Preview · Article · Jan 2013 · European Journal of Immunology
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    ABSTRACT: Dendritic cells (DCs) are antigen-presenting cells efficient in capturing pathogens, and processing their antigenic determinants for presentation to antigen-specific T cells to induce robust immune responses. Their location at peripheral tissues and the expression of pattern-recognition receptors, among them DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), facilitates the capture of pathogens before spreading. However, some pathogens have developed strategies to escape the immune system. One of the most successful is HIV-1, which targets DC-SIGN for transport to the lymph node where the virus infects CD4(+) T cells. Contact of HIV-1 with DC-SIGN is thus the first event in the pathogenic cascade and, therefore, it is the primary target point for therapies aimed at HIV infection prevention. DC-SIGN recognizes specific glycans on HIV-1 and this interaction can be blocked by competitive inhibition through glycans. Although the affinity of glycans is relatively low, multivalency may increase avidity and the strength to compete with HIV-1 virions. We have designed multivalent dendrimeric compounds based on Lewis-type antigens that bind DC-SIGN with high selectivity and avidity and that effectively block gp120 binding to DC-SIGN and, consequently, HIV transmission to CD4(+) T cells. Binding to DC-SIGN and gp120 inhibition was higher on glycodendrimers with larger molecular diameter, indicating that the geometry of the compounds is an important factor determining their functionality. Our compounds elicited DC-SIGN internalization, a property of the receptor upon triggering, but did not affect the maturation status of DCs. Thus, Le(X) glycodendrimers could be incorporated into topic prophylactic approaches for the prevention of HIV-1 transmission.
    No preview · Article · Jan 2013 · International Immunology
  • Linda M van den Berg · Teunis B H Geijtenbeek
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    ABSTRACT: The main route of human immunodeficiency virus-1 (HIV-1) infection is via unprotected sexual intercourse, and therefore, vaginal tissues and male foreskin are viral entry sites. Langerhans cells (LCs) and dendritic cells (DCs) are amongst the first immune cells encountering HIV-1 since these cells line these mucosal tissues. Both LCs and DCs are equipped with specific pattern recognition receptors that not only sense pathogens, but induce specific immune responses against these pathogens. LCs express the C-type lectin receptor langerin, which provides protection against HIV-1 infection. In contrast, DCs express the C-type lectin receptor DC-SIGN, which facilitates capture as well as infection of DCs and subsequent transmission to CD4(+) T cells. This chapter gives an update on immune responses elicited against viruses and sheds a light on different immune mechanisms that are hijacked by HIV-1 to infect the host. HIV-1 infection ultimately leads to the worldwide pandemic acquired immunodeficiency syndrome (AIDS).
    No preview · Article · Jan 2013 · Advances in Experimental Medicine and Biology
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    ABSTRACT: Measles virus (MV) is a highly contagious virus that is transmitted by aerosols. During systemic infection, CD150(+) T and B lymphocytes in blood and lymphoid tissues are the main cells infected by pathogenic MV. However, it is unclear which cell types are the primary targets for MV in the lungs and how the virus reaches the lymphoid tissues. In vitro studies have shown that dendritic cell (DC) C-type lectin DC-SIGN captures MV, leading to infection of DCs as well as transmission to lymphocytes. However, evidence of DC-SIGN-mediated transmission in vivo has not been established. Here we identified DC-SIGN(hi) DCs as first target cells in vivo and demonstrate that macaque DC-SIGN functions as an attachment receptor for MV. Notably, DC-SIGN(hi) cells from macaque broncho-alveolar lavage and lymph nodes transmit MV to B lymphocytes, providing in vivo support for an important role for DCs in both initiation and dissemination of MV infection.
    Full-text · Article · Dec 2012 · PLoS ONE

Publication Stats

14k Citations
1,064.39 Total Impact Points

Institutions

  • 2002-2015
    • University of Amsterdam
      • • Faculty of Medicine AMC
      • • Department of Molecular Cell Biology
      Amsterdamo, North Holland, Netherlands
  • 2002-2013
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Department of Experimental Immunology (EXIM)
      • • Center for Experimental and Molecular Medicine
      Amsterdamo, North Holland, Netherlands
  • 2011
    • Queen's University Belfast
      • Centre for Infection and Immunity
      Belfast, NIR, United Kingdom
  • 2010
    • Imperial College London
      • Department of Life Sciences
      Londinium, England, United Kingdom
    • Erasmus Universiteit Rotterdam
      • Department of Virology
      Rotterdam, South Holland, Netherlands
  • 2002-2009
    • VU University Medical Center
      • Department of Molecular Cell Biology and Immunology
      Amsterdamo, North Holland, Netherlands
    • VU University Amsterdam
      • • Department of Molecular Cell Biology and Immunology
      • • Department of Molecular Cell Biology (MCB)
      Amsterdamo, North Holland, Netherlands
  • 2006
    • University of Wuerzburg
      • Institute for Virology and Immune Biology
      Würzburg, Bavaria, Germany
  • 2003
    • University of Oklahoma Health Sciences Center
      • Department of Biochemistry and Molecular Biology
      Oklahoma City, Oklahoma, United States
  • 2001
    • Case Western Reserve University School of Medicine
      • Department of Pathology
      Cleveland, Ohio, United States
  • 2000-2001
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 1992-2000
    • Utrecht University
      • Centre for Biomembranes and Lipid Enzymology
      Utrecht, Utrecht, Netherlands