Teunis B H Geijtenbeek

University of Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (133)1034.91 Total impact

  • [Show abstract] [Hide abstract]
    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.
    Cell host & microbe. 07/2014; 16(1):19-30.
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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.
    Cell host & microbe. 07/2014; 16(1):31-42.
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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.
    Cell host & microbe 04/2014; 15(4):494-505. · 13.02 Impact Factor
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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.
    Cellular Immunology 03/2014; 289(1-2):49-54. · 1.74 Impact Factor
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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.
    Nature Communications 01/2014; 5:3898. · 10.74 Impact Factor
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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.
    Trends in Parasitology 12/2013; · 5.51 Impact Factor
  • Teunis B H Geijtenbeek, Sonja I Gringhuis
    Nature Immunology 03/2013; 14(4):309-311. · 26.20 Impact Factor
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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.
    International Immunology 01/2013; · 3.14 Impact Factor
  • 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).
    Advances in experimental medicine and biology 01/2013; 762:45-70. · 1.83 Impact Factor
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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.
    European Journal of Immunology 11/2012; · 4.97 Impact Factor
  • Teunis B H Geijtenbeek
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    ABSTRACT: Cell death needs to be detected by immune cells. In this issue of Immunity, Ahrens et al. (2012) and Zhang et al. (2012) show that actin filaments become exposed on necrotic cells and act as ligands for the C-type lectin receptor Clec9a.
    Immunity 04/2012; 36(4):557-9. · 19.80 Impact Factor
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    ABSTRACT: Measles is an important cause of childhood morbidity and mortality in developing countries. Measles virus (MV) is transmitted via the respiratory route and causes systemic disease. Over the last decade, identification of new cellular receptors and studies in animal models have challenged the historic concepts of measles pathogenesis. It is thought that MV enters the host by infection of alveolar macrophages and/or dendritic cells in the airways, and is amplified in local lymphoid tissues. Viremia mediated by infected CD150+ lymphocytes results in systemic dissemination. Infection of lymphocytes and dendritic cells in the respiratory submucosa facilitates basolateral infection of epithelial cells via the newly identified receptor Nectin-4. Concomitant and extensive epithelial damage may contribute to efficient transmission to the next host.
    Current opinion in virology. 04/2012; 2(3):248-55.
  • Linda M van den Berg, Sonja I Gringhuis, Teunis B H Geijtenbeek
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    ABSTRACT: Host-pathogen interactions have coevolved for many years. On the one hand, the human immune system consists of innate and adaptive immune cells that function to defeat pathogens, and on the other hand, pathogens have coevolved to use the system for their own propagation. C-type lectins are conserved receptors recognizing carbohydrate structures on viruses, bacteria, parasites, and fungi. C-type lectins such as DC-SIGN, langerin, and dectin-1 are expressed by dendritic cell subsets and macrophages. Pathogen recognition by C-type lectins triggers signaling pathways that lead to the expression of specific cytokines which subsequently instruct adaptive T helper immune responses. T helper cell differentiation is crucial for initiating proper adaptive immune responses; some pathogens, however, use pattern recognition receptors like C-type lectins to subvert immune responses for survival. This review provides an update on the role of C-type lectins in HIV-1, mycobacterial, and Candida infections, and the coevolution of hosts and pathogens.
    Annals of the New York Academy of Sciences 01/2012; 1253:149-58. · 4.38 Impact Factor
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    ABSTRACT: ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation by cleaving ultra-large VWF multimers on the surfaces of endothelial cells. Autoantibodies directed against ADAMTS13 prohibit the processing of VWF multimers, initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura. The formation of autoantibodies depends on the activation of CD4(+) T cells. This process requires immune recognition, endocytosis, and subsequent processing of ADAMTS13 into peptides that are presented on MHC class II molecules to CD4(+) T cells by dendritic cells (DCs). In the present study, we investigated endocytosis of recombinant ADAMTS13 by immature monocyte-derived DCs using flow cytometry and confocal microscopy. After incubation of fluorescently labeled ADAMTS13 with DCs, significant uptake of ADAMTS13 was observed. Endocytosis of ADAMTS13 was completely blocked by the addition of EGTA and mannan. ADAMTS13 endocytosis was decreased in the presence of a blocking mAb directed toward the macrophage mannose receptor (MR). Furthermore, siRNA silencing of MR reduced the uptake of ADAMTS13 by DCs. In addition, in vitro binding studies confirmed the interaction of ADAMTS13 with the carbohydrate recognition domains of MR. The results of the present study indicate that sugar moieties on ADAMTS13 interact with MR, thereby promoting its endocytosis by APCs.
    Blood 01/2012; 119(16):3828-35. · 9.78 Impact Factor
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    Annelies W Mesman, Teunis B Geijtenbeek
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    ABSTRACT: Dendritic cells (DCs), Langerhans cells (LCs), and macrophages are innate immune cells that reside in genital and intestinal mucosal tissues susceptible to HIV-1 infection. These innate cells play distinct roles in initiation of HIV-1 infection and induction of anti-viral immunity. DCs are potent migratory cells that capture HIV-1 and transfer virus to CD4(+) T cells in the lymph nodes, whereas LCs have a protective anti-viral function, and macrophages function as viral reservoirs since they produce viruses over prolonged times. These differences are due to the different immune functions of these cells partly dependent on the expression of specific pattern recognition receptors. Expression of Toll-like receptors, C-type lectin receptors, and cell-specific machinery for antigen uptake and processing strongly influence the outcome of virus interactions.
    Frontiers in Immunology 01/2012; 3:59.
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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.
    PLoS ONE 01/2012; 7(12):e49573. · 3.53 Impact Factor
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    ABSTRACT: Production of the proinflammatory cytokine interleukin 1β (IL-1β) by dendritic cells is crucial in host defense. Here we identify a previously unknown role for dectin-1 in the activation of a noncanonical caspase-8 inflammasome in response to fungi and mycobacteria. Dectin-1 induced both the production and maturation of IL-1β through signaling routes mediated by the kinase Syk. Whereas the CARD9-Bcl-10-MALT1 scaffold directed IL1B transcription, the recruitment of MALT1-caspase-8 and ASC into this scaffold was crucial for processing of pro-IL-1β by caspase-8. In contrast to activation of the canonical caspase-1 inflammasome, which requires additional activation of cytosolic receptors, activation of the noncanonical caspase-8 inflammasome was independent of pathogen internalization. Thus, dectin-1 acted as an extracellular sensor for pathogens that induced both IL-1β production and maturation through a noncanonical caspase-8-dependent inflammasome for protective immunity.
    Nature Immunology 01/2012; 13(3):246-54. · 26.20 Impact Factor
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    ABSTRACT: This review summarizes the current knowledge of innate signaling events that are involved in HIV-1 infection. We here focus on dendritic cells, which are among the first cells that encounter HIV-1 after exposure. HIV-1 triggers multiple pattern recognition receptors on dendritic cells that facilitate infection and transmission to T cells. Triggering of the C-type lectin DC-SIGN induces signals that promote HIV-1 replication in dendritic cells and transmission to T cells. Similarly, dendritic cell immunoreceptor has been shown to bind HIV-1 and facilitate transmission to T cells. The cytosolic sensors TRIM5 and cyclophilin A recognize capsid proteins and activate antiviral responses to prevent HIV-1 infection. Moreover, activation of mammalian target of rapamycin (mTOR) by HIV downregulates autophagy preventing adaptive immune responses. Dendritic cells express an array of pattern recognition receptors that are involved in HIV-1 infection. However, HIV-1 dampens signaling by these receptors leading to suppressed responses or takes advantage of their signaling for its own benefit.
    Current opinion in HIV and AIDS 09/2011; 6(5):348-52. · 4.75 Impact Factor
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    ABSTRACT: Langerhans cells (LCs) are a subset of DCs that reside in the upper respiratory tract and are ideally suited to sense respiratory virus infections. Measles virus (MV) is a highly infectious lymphotropic and myelotropic virus that enters the host via the respiratory tract. Here, we show that human primary LCs are capable of capturing MV through the C-type lectin Langerin. Both immature and mature LCs presented MV-derived antigens in the context of HLA class II to MV-specific CD4(+) T cells. Immature LCs were not susceptible to productive infection by MV and did not present endogenous viral antigens in the context of HLA class I. In contrast, mature LCs could be infected by MV and presented de novo synthesized viral antigens to MV-specific CD8(+) T cells. Notably, neither immature nor mature LCs were able to cross-present exogenous UV-inactivated MV or MV-infected apoptotic cells. The lack of direct infection of immature LCs, and the inability of both immature and mature LCs to cross-present MV antigens, suggest that human LCs may not be directly involved in priming MV-specific CD8(+) T cells. Immune activation of LCs seems a prerequisite for MV infection of LCs and subsequent CD8(+) T-cell priming via the endogenous antigen presentation pathway.
    European Journal of Immunology 07/2011; 41(9):2619-31. · 4.97 Impact Factor
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    ABSTRACT: Human skin contains epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) that are key players in induction of adaptive immunity upon infection. After major burn injury, suppressed adaptive immunity has been observed in patients. Here we demonstrate that burn injury affects adaptive immunity by altering both epidermal LC and dermal DC functions. We developed a human ex vivo burn injury model to study the function of DCs in thermally injured skin. No differences were observed in the capacity of both LCs and dermal DCs to migrate out of burned skin compared to unburned skin. Similarly, expression levels of co-stimulatory molecules were unaltered. Notably, we observed a strong reduction of T cell activation induced by antigen presenting cell (APC) subsets that migrated from burned skin through soluble burn factors. Further analyses demonstrated that both epidermal LCs and dermal DCs have a decreased T cell stimulatory capacity after burn injury. Restoring the T cell stimulatory capacity of DC subsets might improve tissue regeneration in patients with burn wounds.
    Cellular Immunology 02/2011; 268(1):29-36. · 1.74 Impact Factor

Publication Stats

9k Citations
1,034.91 Total Impact Points

Institutions

  • 2005–2014
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
  • 2002–2013
    • VU University Medical Center
      • Department of Molecular Cell Biology and Immunology
      Amsterdam, North Holland, Netherlands
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Department of Experimental Immunology (EXIM)
      • • Academic Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2011
    • Queen's University Belfast
      • Centre for Infection and Immunity
      Belfast, NIR, United Kingdom
  • 2010
    • Erasmus Universiteit Rotterdam
      • Department of Virology
      Rotterdam, South Holland, Netherlands
  • 2007–2010
    • Erasmus MC
      • Department of Virology
      Rotterdam, South Holland, Netherlands
  • 2001–2009
    • VU University Amsterdam
      • • Department of Molecular Cell Biology and Immunology
      • • Department of Molecular Cell Biology (MCB)
      Amsterdam, North Holland, Netherlands
  • 2008
    • Westmead Millennium Institute
      Sydney, New South Wales, Australia
  • 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
  • 2000–2001
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands