Esther C de Jong

Publications of Esther C de Jong

• CD5 costimulation induces stable Th17 development by promoting IL-23R expression and sustained STAT3 activation.

  Authors: Jelle de Wit, Yuri Souwer, Astrid J van Beelen, Rosa de Groot, Femke J M Muller, Hanny Klaasse Bos, Tineke Jorritsma, Martien L Kapsenberg, Esther C de Jong, S Marieke van Ham

  Blood. 09/2011; 118(23):6107-14.

  IL-17-producing CD4(+) T helper (Th17) cells are important for immunity against extracellular pathogens and in autoimmune diseases. The factors that drive Th17 development in human remain a matter ofIL-17-producing CD4(+) T helper (Th17) cells are important for immunity against extracellular pathogens and in autoimmune diseases. The factors that drive Th17 development in human remain a matter of debate. Here we show that, compared with classic CD28 costimulation, alternative costimulation via the CD5 or CD6 lymphocyte receptors forms a superior pathway for human Th17-priming. In the presence of the Th17-promoting cytokines IL-1β, IL-6, IL-23, and transforming growth factor-β (TGF-β), CD5 costimulation induces more Th17 cells that produce higher amounts of IL-17, which is preceded by prolonged activation of signal transducer and activator of transcription 3 (STAT3), a key regulator in Th17 differentiation, and enhanced levels of the IL-17-associated transcription factor retinoid-related orphan receptor-γt (ROR-γt). Strikingly, these Th17-promoting signals critically depend on CD5-induced elevation of IL-23 receptor (IL-23R) expression. The present data favor the novel concept that alternative costimulation via CD5, rather than classic costimulation via CD28, primes naive T cells for stable Th17 development through promoting the expression of IL-23R.

• Cutting edge: virus selectively primes human langerhans cells for CD70 expression promoting CD8+ T cell responses.

  Authors: Angelic M G van der Aar, Rosa de Groot, Marta Sanchez-Hernandez, Esther W M Taanman, René A W van Lier, Marcel B M Teunissen, Esther C de Jong, Martien L Kapsenberg

  Journal of immunology (Baltimore, Md. : 1950). 08/2011; 187(7):3488-92.

  The two outermost compartments of skin are populated by different Ag-presenting dendritic cell types. Epidermal Langerhans cells (LCs) are evolutionarily adapted to the continuous presence ofThe two outermost compartments of skin are populated by different Ag-presenting dendritic cell types. Epidermal Langerhans cells (LCs) are evolutionarily adapted to the continuous presence of harmless skin commensals by the selective lack of cell surface TLRs that sense bacteria. In this article, we analyze the ability of LCs and dermal dendritic cells (DDCs) to respond to virus infection. Live virus and intracellular TLR3-agonist dsRNA commit LCs more effectively than DDCs to stimulate naive CD8(+) T cell expansion and their differentiation into effector cells. This potent CD8(+) T cell-promoting capacity of LCs is causally related to high levels of virus-induced CD70 expression but not to IL-12 production. These data suggest a remarkable specialization of LCs in the induction of pathogen class-specific adaptive immunity. Whereas LCs ignore bacteria, they are superior to DDCs to initiate effective CD70-mediated CD8(+) T cells in response to virus stimulation.

• Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T cells.

  Authors: Angelic M G van der Aar, Darya S Sibiryak, Ghaith Bakdash, Toni M M van Capel, Hanneke P M van der Kleij, Dirk-Jan E Opstelten, Marcel B M Teunissen, Martien L Kapsenberg, Esther C de Jong

  The Journal of allergy and clinical immunology. 06/2011; 127(6):1532-40.e7.

  The vitamin D metabolite 1,25(OH)2D3 (VitD3) is a potent immunosuppressive drug and, among others, is used for topical treatment of psoriasis. A proposed mechanism of VitD3-mediated suppression isThe vitamin D metabolite 1,25(OH)2D3 (VitD3) is a potent immunosuppressive drug and, among others, is used for topical treatment of psoriasis. A proposed mechanism of VitD3-mediated suppression is priming of dendritic cells (DCs) to induce regulatory T (Treg) cells. Currently, there is confusion about the phenotype of VitD3-induced Treg cells and the DC-derived molecules driving their development. We investigated Treg cell induction after VitD3 priming of 2 distinct skin DC subsets: Langerhans cells (LCs) and dermal dendritic cells (DDCs). LCs and DDCs primed with VitD3 were cocultured with allogeneic naive T cells. The phenotype and function of the DCs and induced T cells were analyzed. Both VitD3-primed DC subtypes induced T cells with regulatory activity. Unexpectedly, whereas the Treg cell populations generated by VitD3-primed LCs were CD25(hi)CD127(lo) forkhead box protein 3 (Foxp3)-positive cells, which meet the criteria of classical inducible Treg cells, the T cells developing in response to VitD3-primed DDCs were Foxp3(-) T(R)1 cells expressing IL-10. Inhibition experiments revealed that LC-derived TGF-β is a key factor in the induction of Foxp3(+) Treg cells, whereas DDC-derived IL-10 is important for the induction of IL-10(+) T(R)1 cells. Thus we report the novel finding that distinct but closely related DC subsets are differentially programmed by VitD3 to support development of either TGF-β-dependent Foxp3(+) Treg cells or IL-10-dependent IL-10(+) Treg cells.

• Skin-depigmenting agent monobenzone induces potent T-cell autoimmunity toward pigmented cells by tyrosinase haptenation and melanosome autophagy.

  Authors: Jasper G van den Boorn, Daisy I Picavet, Paul F van Swieten, Henk A van Veen, Debby Konijnenberg, Peter A van Veelen, Toni van Capel, Esther C de Jong, Eric A Reits, Jan W Drijfhout, Jan D Bos, Cornelis J M Melief, Rosalie M Luiten

  The Journal of investigative dermatology. 02/2011; 131(6):1240-51.

  In this study, we report the previously unknown mechanism of inducing robust anti-melanoma immunity by the vitiligo-inducing compound monobenzone. We show monobenzone to increase melanocyte andIn this study, we report the previously unknown mechanism of inducing robust anti-melanoma immunity by the vitiligo-inducing compound monobenzone. We show monobenzone to increase melanocyte and melanoma cell immunogenicity by forming quinone-haptens to the tyrosinase protein and by inducing the release of tyrosinase- and melanoma antigen recognized by T cells-1 (MART-1)-containing CD63+ exosomes following melanosome oxidative stress induction. Monobenzone further augments the processing and shedding of melanocyte-differentiation antigens by inducing melanosome autophagy and enhanced tyrosinase ubiquitination, ultimately activating dendritic cells, which induced cytotoxic human melanoma-reactive T cells. These T cells effectively eradicate melanoma in vivo, as we have reported previously. Monobenzone thereby represents a promising and readily applicable compound for immunotherapy in melanoma patients.

• Selective C-Rel activation via Malt1 controls anti-fungal T(H)-17 immunity by dectin-1 and dectin-2.

  Authors: Sonja I Gringhuis, Brigitte A Wevers, Tanja M Kaptein, Toni M M van Capel, Bart Theelen, Teun Boekhout, Esther C de Jong, Teunis B H Geijtenbeek

  PLoS pathogens. 01/2011; 7(1):e1001259.

  C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of T(H)1 and T(H)-17 cellular responses. Fungal recognition by dectin-1C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of T(H)1 and T(H)-17 cellular responses. Fungal recognition by dectin-1 on human dendritic cells engages the CARD9-Bcl10-Malt1 module to activate NF-κB. Here we demonstrate that Malt1 recruitment is pivotal to T(H)-17 immunity by selective activation of NF-κB subunit c-Rel, which induces expression of T(H)-17-polarizing cytokines IL-1β and IL-23p19. Malt1 inhibition abrogates c-Rel activation and T(H)-17 immunity to Candida species. We found that Malt1-mediated activation of c-Rel is similarly essential to induction of T(H)-17-polarizing cytokines by dectin-2. Whereas dectin-1 activates all NF-κB subunits, dectin-2 selectively activates c-Rel, signifying a specialized T(H)-17-enhancing function for dectin-2 in anti-fungal immunity by human dendritic cells. Thus, dectin-1 and dectin-2 control adaptive T(H)-17 immunity to fungi via Malt1-dependent activation of c-Rel.

• IL-17 and IL-22 in atopic allergic disease.

  Authors: Yuri Souwer, Krisztina Szegedi, Martien L Kapsenberg, Esther C de Jong

  Current opinion in immunology. 11/2010; 22(6):821-6.

  A long standing paradigm is that antigen-specific Th2 cells and their cytokines such as IL-4, IL-5, and IL-13 orchestrate the characteristic features of atopic allergy. The discovery of a role forA long standing paradigm is that antigen-specific Th2 cells and their cytokines such as IL-4, IL-5, and IL-13 orchestrate the characteristic features of atopic allergy. The discovery of a role for IL-17-producing (Th17) and IL-22-producing (Th22) T helper cells in inflammatory diseases has added an additional layer of complexity to the understanding of the pathogenesis of allergic diseases. Here we re-evaluate the role of T helper cells, with special focus on the Th17 and Th22 subsets in allergic asthma and atopic dermatitis. Whereas sparse data point to a protective role of the increasing amounts of Th22 cells that are found in chronic stages of both allergies, the data on Th17 cells paint different pictures for the contribution of Th17 cells during subsequent stages of these two forms of allergy.

• Aberrant function of peripheral blood myeloid and plasmacytoid dendritic cells in atopic dermatitis patients.

  Authors: M Cristina Lebre, Toni M M van Capel, Jan D Bos, Edward F Knol, Martien L Kapsenberg, Esther C de Jong

  The Journal of allergy and clinical immunology. 11/2008;

  BACKGROUND: Dendritic cells (DCs) can act both as innate cells in host defense and as antigen-presenting cells for naive T cells in adaptive immunity. These functions, among others, are determined byBACKGROUND: Dendritic cells (DCs) can act both as innate cells in host defense and as antigen-presenting cells for naive T cells in adaptive immunity. These functions, among others, are determined by the level of production of particular cytokines. Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by an initial phase predominated by T(H)2 cytokines that switches into a second, more chronic T(H)1-dominated eczematous phase. OBJECTIVE: To assess to what extent the AD phenotype is associated with an aberrant phenotype and function of DCs. METHODS: Classic CD1c(+)/blood DC antigen (BDCA)-1(+) myeloid (m) DCs and CD304(+)/BDCA4(+) plasmacytoid (p) DCs, the natural IFN-producing cells, were isolated from peripheral blood of patients with AD and healthy controls and analyzed for their phenotype and function. RESULTS: Purified CD1c(+)/BDCA1(+) mDCs from patients with AD showed a selective and dramatic reduction of IL-12p70 and TNF-alpha release. IL-12p70 reduction was attributed to a defective expression of both IL-12p35 and IL-12p40 subunits. Accordingly, mature CD1c(+)/BDCA1(+) mDCs from patients with AD induced considerably less IFN-gamma-producing and more IL-4-producing T(H) cells compared with mDCs from healthy controls. In addition, CD304(+)/BDCA4(+) pDCs from patients with AD produced significantly lower levels of IFN-alpha compared with healthy controls. CONCLUSION: Myeloid DCs and pDCs from patients with AD show defective IL-12, TNF-alpha, and IFN-alpha production, which may contribute to increased susceptibility to infection and to the maintenance of the T(H)2 cell-mediated allergic state in patients with AD.

• Muramyl dipeptide-induced differential gene expression in NOD2 mutant and wild-type Crohn's disease patient-derived dendritic cells.

  Authors: Zuzana Zelinkova, Astrid J van Beelen, Floor de Kort, Perry D Moerland, Emiel Ver Loren van Themaat, Anje A te Velde, Sander J van Deventer, Esther C de Jong, Daniel W Hommes

  Inflammatory bowel diseases. 03/2008; 14(2):186-94.

  BACKGROUND: Mutations in the gene encoding the nucleotide-binding oligomerization domain 2 (NOD2) protein are associated with Crohn's disease (CD), but the mechanism underlying this is not completelyBACKGROUND: Mutations in the gene encoding the nucleotide-binding oligomerization domain 2 (NOD2) protein are associated with Crohn's disease (CD), but the mechanism underlying this is not completely understood. To study the mechanism of CD resulting from NOD2 mutations, we analyzed NOD2-dependent whole-genome expression profiles of patient-derived antigen-presenting cells. PATIENTS AND METHODS: Monocyte-derived dendritic cells (DCs) from CD carriers of double-dose NOD2 mutations, wild-type CD patients, and wild-type healthy volunteers were stimulated with the NOD2 ligand muramyl dipeptide. Whole-genome microarrays were used to assess the differential gene expression. The clustering of significantly changed genes was analyzed by online gene ontology mapping software. RESULTS: In the DCs from the wild-type CD patient group, 683 genes were significantly changed, with most of the genes clustering in the pathways of inflammatory response. In addition, a significant number of genes clustered in the apoptosis regulation-related pathway. In the DCs from the healthy volunteer group, only 50 genes were significantly changed, predominantly those belonging to the response to pathogen pathway. Analysis of differentially expressed gene ontology pathways in the DCs from the NOD2 mutant CD patient group showed that the transcription of pathogen response genes was absent. In this group, 298 genes were significantly changed, predominantly clustering in the negative apoptosis regulation and cell organization and biogenesis pathways. CONCLUSIONS: Our results suggest that NOD2 mutations may result in perpetuation of mucosal inflammation through insufficient pathogen elimination. Further, these observations implicate a possible role of defective regulation of dendritic cell apoptosis in CD pathogenesis.

• Interleukin-17 in inflammatory skin disorders.

  Authors: Astrid J van Beelen, Marcel B M Teunissen, Martien L Kapsenberg, Esther C de Jong

  Current opinion in allergy and clinical immunology. 11/2007; 7(5):374-81.

  PURPOSE OF REVIEW: Recently, a novel and unique subset of interleukin (IL)-17-producing CD4+ T helper (Th17) cells, distinct from Th1 and Th2 cells, was discovered. The question is addressed as toPURPOSE OF REVIEW: Recently, a novel and unique subset of interleukin (IL)-17-producing CD4+ T helper (Th17) cells, distinct from Th1 and Th2 cells, was discovered. The question is addressed as to what extent inflammatory skin diseases are associated with the actions of this newly discovered Th17 cell subset. RECENT FINDINGS: Th17 cells are involved in protection against bacterial pathogens. In addition, it is now clear that Th17 cells may also be crucial in the pathogenesis of various chronic inflammatory diseases that were formerly categorized as Th1-mediated disorders. SUMMARY: In this review, we summarize the current knowledge of IL-17 and Th17 cells and discuss the possible role of IL-17 in the pathology of psoriasis, contact hypersensitivity and atopic dermatitis. Whereas IL-17 may play an important role in the pathogenesis of psoriasis and contact hypersensitivity, its role in atopic dermatitis is still unclear.

• Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells.

  Authors: Astrid J van Beelen, Zuzana Zelinkova, Esther W Taanman-Kueter, Femke J Muller, Daniel W Hommes, Sebastian A J Zaat, Martien L Kapsenberg, Esther C de Jong

  Immunity. 11/2007; 27(4):660-9.

  How the development of antibacterial T helper 17 (Th17) cells is selectively promoted by antigen-presenting dendritic cells (DCs) is unclear. We showed that bacteria, but not viruses, primed humanHow the development of antibacterial T helper 17 (Th17) cells is selectively promoted by antigen-presenting dendritic cells (DCs) is unclear. We showed that bacteria, but not viruses, primed human DCs to promote IL-17 production in memory Th cells through the nucleotide oligomerization domain 2 (NOD2)-ligand muramyldipeptide (MDP), a derivative of bacterial peptidoglycan. MDP enhanced obligate bacterial Toll-like receptor (TLR) agonist induction of IL-23 and IL-1, which promoted IL-17 expression in T cells. The role of NOD2 in this IL-23-IL-1-IL-17 axis could be confirmed in NOD2-deficient DCs, such as DCs from selected Crohn's disease patients. Thus, antibacterial Th17-mediated immunity in humans is orchestrated by DCs upon sensing bacterial NOD2-ligand MDP.

• Monocyte-derived dendritic cells from chronic HCV patients are not infected but show an immature phenotype and aberrant cytokine profile.

  Authors: Huub C Gelderblom, Laurens E J Nijhuis, Esther C de Jong, Anje A te Velde, Dasja Pajkrt, Henk W Reesink, Marcel G H M Beld, Sander J H van Deventer, Peter L M Jansen

  Liver international : official journal of the International Association for the Study of the Liver. 10/2007; 27(7):944-53.

  BACKGROUND: Chronic hepatitis C virus (HCV) infection is characterized by an insufficient immune response, possibly owing to impaired function of antigen-presenting cells such as myeloid dendriticBACKGROUND: Chronic hepatitis C virus (HCV) infection is characterized by an insufficient immune response, possibly owing to impaired function of antigen-presenting cells such as myeloid dendritic cells (DCs). Therapeutic vaccination with in vitro generated DCs may enhance the immune response. Subsets of DCs can originate from monocytes, but the presence of HCV in monocytes that develop into DCs in vitro may impair DC function. Therefore, we studied the presence of HCV RNA in monocytes and monocyte-derived DCs from chronic HCV patients. METHODS: Monocytes were cultured with granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) for 6 days, and then with GM-CSF, IL-4, tumour necrosis factor-alpha (TNF-alpha), prostaglandin E2, IL-1beta and IL-6 for 2 days to generate mature DCs. HCV RNA was assessed by polymerase chain reaction. Surface molecules were assessed by flow cytometry. Cytokine production was assessed by cytokine bead array. RESULTS: HCV RNA was present in monocytes in 11 of 13 patients, but undetectable in mature DCs in 13 of 13 patients. The morphology of patient DCs was comparable with DCs from healthy controls, but the percentage of cells expressing surface molecules CD83 (P=0.001), CD86 (P=0.023) and human leucocyte antigen-DR (P=0.028) was lower in HCV patients. Compared with control DCs, patient DCs produced enhanced levels of IL-10 (P=0.0079) and IL-8 (P=0.0079), and lower levels of TNF-alpha (P=0.032), IL-6 (P=NS) and IL-1beta (P=0.0079). Patient and control DCs did not produce IL-12. CONCLUSIONS: Monocyte-derived DCs from chronic HCV patients are not infected but show an immature phenotype and aberrant cytokine profile.

• Noncanonical NF-kappaB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation.

  Authors: Sander W Tas, Margriet J Vervoordeldonk, Najat Hajji, Joost H N Schuitemaker, Koen F van der Sluijs, Michael J May, Sankar Ghosh, Martien L Kapsenberg, Paul P Tak, Esther C de Jong

  Blood. 10/2007; 110(5):1540-9.

  Ligation of CD40 on dendritic cells (DCs) induces early production of inflammatory mediators via canonical NF-kappaB signaling, as well as late expression of the anti-inflammatory enzyme indoleamineLigation of CD40 on dendritic cells (DCs) induces early production of inflammatory mediators via canonical NF-kappaB signaling, as well as late expression of the anti-inflammatory enzyme indoleamine 2,3-dioxygenase (IDO) via unknown signal transduction. By selective blocking of either the canonical NF-kappaB pathway using the NEMO-binding domain peptide or the noncanonical NF-kappaB pathway by small interfering RNA, we demonstrate that IDO expression requires noncanonical NF-kappaB signaling. Also, noncanonical NF-kappaB signaling down-regulates proinflammatory cytokine production in DCs. In addition, selective activation of the noncanonical NF-kappaB pathway results in noninflammatory DCs that suppress T-cell activation and promote the development of T cells with regulatory properties. These findings reveal an important role of the noncanonical NF-kappaB pathway in the regulation of immunity.

• Loss of TLR2, TLR4, and TLR5 on Langerhans cells abolishes bacterial recognition.

  Authors: Angelic M G van der Aar, Regien M R Sylva-Steenland, Jan D Bos, Martien L Kapsenberg, Esther C de Jong, Marcel B M Teunissen

  Journal of immunology (Baltimore, Md. : 1950). 03/2007; 178(4):1986-90.

  It is unknown whether closely related epidermal dendritic cells, Langerhans cells (LCs), and dermal dendritic cells (DDCs) have unique functions. In this study, we show that human DDCs have a broadIt is unknown whether closely related epidermal dendritic cells, Langerhans cells (LCs), and dermal dendritic cells (DDCs) have unique functions. In this study, we show that human DDCs have a broad TLR expression profile, whereas human LCs have a selective impaired expression of cell surface TLR2, TLR4, and TLR5, all involved in bacterial recognition. This distinct TLR expression profile is acquired during the TGF-beta1-driven development of LCs in vitro. Consequently, and in contrast to DDCs, LCs weakly respond to bacterial TLR2, TLR4, and TLR5 ligands in terms of cytokine production and maturation, as well as to whole Gram-positive and Gram-negative bacteria, whereas their responsiveness to viral TLR ligands and viruses is fully active and comparable to DDCs. Unresponsiveness of LCs to bacteria may be a mechanism that contributes to tolerance to bacterial commensals that colonize the skin.

• Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9.

  Authors: Maria C Lebre, Angelic M G van der Aar, Lisa van Baarsen, Toni M M van Capel, Joost H N Schuitemaker, Martien L Kapsenberg, Esther C de Jong

  The Journal of investigative dermatology. 03/2007; 127(2):331-41.

  Keratinocytes are continuously in contact with external stimuli and have the capacity to produce several soluble mediators. Pathogen-associated molecular patterns (PAMPs) are recognized, amongKeratinocytes are continuously in contact with external stimuli and have the capacity to produce several soluble mediators. Pathogen-associated molecular patterns (PAMPs) are recognized, among others, by Toll-like receptors (TLRs). The functional responses of keratinocytes to different PAMPs have not yet been fully established. Here we show that keratinocytes constitutively express TLR1, 2, 3, 4, 5, 6, 9, and 10 mRNA, but not TLR7 and 8. Stimulation of keratinocytes with TLR3, 4, 5, and 9 ligands resulted in differential immune-associated responses. Tumor necrosis factor-alpha, CXC chemokine ligand 8 (CXCL8), CCL2, and C chemokine ligand 20 (CCL20) release was enhanced in response to all PAMPs tested, in a time- and dose-dependent manner. Only TLR9 ligand CpG-oligodeoxynucleotides (ODNs) and TLR3 ligand poly-I:C could additionally induce type I IFNs. CCL27 production was selectively induced by poly-I:C and flagellin, whereas CXCL9 and CXCL10 were exclusively induced by CpG-ODNs and/or poly-I:C. Upregulation of ICAM-1, HLA-DR, HLA-ABC, FasR, and CD40 was mainly observed in response to poly-I:C, flagellin, and lipopolysaccharide. Furthermore, PAMP triggering resulted in the phosphorylation of phosphorylated-IkappaB alpha and in the nucleus translocation of NF-kappaB p65. Altogether, these findings stress an unexpectedly multifaceted role of keratinocytes in innate immunity as evident by their differential, TLR-mediated responses to PAMPs associated with different classes of pathogens.

• Opposing roles of blood myeloid and plasmacytoid dendritic cells in HIV-1 infection of T cells: transmission facilitation versus replication inhibition.

  Authors: Fedde Groot, Toni M M van Capel, Martien L Kapsenberg, Ben Berkhout, Esther C de Jong

  Blood. 10/2006; 108(6):1957-64.

  CD11c(+) myeloid dendritic cells (MDCs) and CD11c(-) CD123(+) plasmacytoid DCs (PDCs) have been identified as main human DC subsets. MDCs are professional antigen-presenting cells for T cells, andCD11c(+) myeloid dendritic cells (MDCs) and CD11c(-) CD123(+) plasmacytoid DCs (PDCs) have been identified as main human DC subsets. MDCs are professional antigen-presenting cells for T cells, and include Langerhans cells, dermal DCs, and interstitial DCs. They have been associated with HIV-1 capture and sexual transmission, whereas PDCs play an important role in the innate immune responses to different types of viruses, including HIV-1. To compare the influence of MDCs and PDCs on HIV-1 infection of T cells, we isolated donor-matched MDCs and PDCs from peripheral blood, activated them by adding different maturation-inducing compounds, and cocultured them with T cells and HIV-1. We found that MDCs enhance HIV-1 infection through capture of the virus and subsequent transmission to T cells, and that differently matured MDC subsets have different HIV-1 transmission efficiencies. These differences were not due to soluble factors, viral capture differences, or the expression of integrins ICAM-1, -2, -3, or LFA-1. In contrast, regardless of their state of maturation, PDCs inhibit HIV-1 replication in T cells through the secretion of IFNalpha and an additional, unidentified small molecule. This study shows that the 2 main types of DCs have opposing roles in HIV-1 infection of T cells.

• Dendritic cell-mediated HIV-1 transmission to T cells of LAD-1 patients is impaired due to the defect in LFA-1.

  Authors: Fedde Groot, Taco W Kuijpers, Ben Berkhout, Esther C de Jong

  Retrovirology. 02/2006; 3:75.

  BACKGROUND: Dendritic cells (DC) have been proposed to mediate sexual HIV-1 transmission by capturing the virus in the mucosa and subsequently presenting it to CD4+ T cells. We have demonstratedBACKGROUND: Dendritic cells (DC) have been proposed to mediate sexual HIV-1 transmission by capturing the virus in the mucosa and subsequently presenting it to CD4+ T cells. We have demonstrated before that DC subsets expressing higher levels of intercellular adhesion molecule-1 (ICAM-1) are better HIV-1 transmitters. ICAM-1 binds leukocyte function-associated molecule-1 (LFA-1) on T cells, an integrin responsible for adhesion and signaling at the immunological synapse. To corroborate the importance of the ICAM-1- LFA-1 interaction, we performed transmission experiments to LFA-1 negative leukocytes from Leukocyte Adhesion Deficiency type 1 (LAD-1) patients. RESULTS: We clearly show that DC-mediated HIV-1 transmission to LAD-1 T cells is impaired in comparison to healthy controls. Furthermore, HIV-1 transmission to T cells from a unique LAD-1 patient with a well characterized LFA-1 activation defect was impaired as well, demonstrating that activation of LFA-1 is crucial for efficient transmission. Decreased cell adhesion between DC and LAD-1 T cells could also be illustrated by significantly smaller DC-T cell clusters after HIV-1 transmission. CONCLUSION: By making use of LFA-1 defect cells from unique patients, this study provides more insight into the mechanism of HIV-1 transmission by DC. This may offer new treatment options to reduce sexual transmission of HIV-1.

• Differential susceptibility of naïve, central memory and effector memory T cells to dendritic cell-mediated HIV-1 transmission.

  Authors: Fedde Groot, Toni M M van Capel, Joost Schuitemaker, Ben Berkhout, Esther C de Jong

  Retrovirology. 02/2006; 3:52.

  BACKGROUND: Dendritic cells (DC) have been proposed to facilitate sexual transmission of HIV-1 by capture of the virus in the mucosa and subsequent transmission to CD4+ T cells. Several T cellBACKGROUND: Dendritic cells (DC) have been proposed to facilitate sexual transmission of HIV-1 by capture of the virus in the mucosa and subsequent transmission to CD4+ T cells. Several T cell subsets can be identified in humans: naïve T cells (TN) that initiate an immune response to new antigens, and memory T cells that respond to previously encountered pathogens. The memory T cell pool comprises central memory (TCM) and effector memory cells (TEM), which are characterized by distinct homing and effector functions. The TEM cell subset, which can be further divided into effector Th1 and Th2 cells, has been shown to be the prime target for viral replication after HIV-1 infection, and is abundantly present in mucosal tissues. RESULTS: We determined the susceptibility of TN, TCM and TEM cells to DC-mediated HIV-1 transmission and found that co-receptor expression on the respective T cell subsets is a decisive factor for transmission. Accordingly, CCR5-using (R5) HIV-1 was most efficiently transmitted to TEM cells, and CXCR4-using (X4) HIV-1 was preferentially transmitted to TN cells. CONCLUSION: The highly efficient R5 transfer to TEM cells suggests that mucosal T cells are an important target for DC-mediated transmission. This may contribute to the initial burst of virus replication that is observed in these cells. TN cells, which are the prime target for DC-mediated X4 virus transmission in our study, are considered to inefficiently support HIV-1 replication. Our results thus indicate that DC may play a decisive role in the susceptibility of TN cells to X4 tropic HIV-1.

• Future perspectives of novel immunomodulating substances in immunotherapy.

  Authors: Esther C de Jong, Martien L Kapsenberg

  Arbeiten aus dem Paul-Ehrlich-Institut (Bundesamt für Sera und Impfstoffe) zu Frankfurt a.M. 01/2006;

• Analysis of anthrax and plague biowarfare vaccine interactions with human monocyte-derived dendritic cells.

  Authors: Anna Skowera, Esther C de Jong, Joost H N Schuitemaker, Jennifer S Allen, Simon C Wessely, Gareth Griffiths, Martien Kapsenberg, Mark Peakman

  Journal of immunology (Baltimore, Md. : 1950). 01/2006; 175(11):7235-43.

  The anti-biowarfare anthrax and plague vaccines require repeated dosing to achieve adequate protection. To test the hypothesis that this limited immunogenicity results from the nature of vaccineThe anti-biowarfare anthrax and plague vaccines require repeated dosing to achieve adequate protection. To test the hypothesis that this limited immunogenicity results from the nature of vaccine interactions with the host innate immune system, we investigated molecular and cellular interactions between vaccines, dendritic cells (DCs), and T cells and explored the potential for adjuvants (pertussis) to boost induction of host immunity. Human monocyte-derived DCs were matured in the presence of vaccines and analyzed for their ability to induce Th1/Th2 development from naive T cells, expression of cell surface maturation/costimulation molecules, and cytokine production. The vaccines showed different behavior patterns. Although the plague vaccine is equivalent to control maturation factors in maturation and stimulation of DCs and induces strong MLR and Th outgrowth, the anthrax vaccine is a poor inducer of DC maturation, as indicated by low levels of HLA-DR, CD86, and CD83 induction and minimal proinflammatory cytokine production. Interestingly, however, anthrax vaccine-treated DCs stimulate Th1 and Th2 outgrowth and a limited MLR response. There was no sustained negative modulatory effects of the anthrax vaccine on DCs, and its limited stimulatory effects could be overridden by coculture with pertussis. These results were supported by analysis of anthrax vaccine recall responses in subjects vaccinated using pertussis as an adjuvant, who demonstrate anthrax-specific effector T cell responses. These data show that the anthrax vaccine is a suboptimal DC stimulus that may in part explain the observation that it requires repeated administration in vivo and offer a rational basis for the use of complementary DC-maturing adjuvants in combined immunotherapy.

• Differential expression of inflammatory chemokines by Th1- and Th2-cell promoting dendritic cells: a role for different mature dendritic cell populations in attracting appropriate effector cells to peripheral sites of inflammation.

  Authors: M Cristina Lebre, Tim Burwell, Pedro L Vieira, Jose Lora, Anthony J Coyle, Martien L Kapsenberg, Björn E Clausen, Esther C de Jong

  Immunology and cell biology. 11/2005; 83(5):525-35.

  Protective immunity to pathogens depends on efficient immune responses adapted to the type of pathogen and the infected tissue. Dendritic cells (DC) play a pivotal role in directing the effector TProtective immunity to pathogens depends on efficient immune responses adapted to the type of pathogen and the infected tissue. Dendritic cells (DC) play a pivotal role in directing the effector T cell response to either a protective T helper type 1 (Th1) or type 2 (Th2) phenotype. Human monocyte-derived DC can be differentiated into Th1-, Th2- or Th1/Th2-promoting DC in vitro upon activation with microbial compounds or cytokines. Host defence is highly dependent on mobile leucocytes and cell trafficking is largely mediated by the interactions of chemokines with their specific receptors expressed on the surface of leucocytes. The production of chemokines by mature effector DC remains elusive. Here we assess the differential production of both inflammatory and homeostatic chemokines by monocyte-derived mature Th1/Th2-, Th1- or Th2-promoting DC and its regulation in response to CD40 ligation, thereby mimicking local engagement with activated T cells. We show that mature Th1- and Th1/Th2-, but not Th2-promoting DC, selectively express elevated levels of the inflammatory chemokines CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta and CCL5/RANTES, as well as the homeostatic chemokine CCL19/MIP-3beta. CCL21/6Ckine is preferentially expressed by Th2-promoting DC. Production of the Th1-attracting chemokines, CXCL9/Mig, CXCL10/IP-10 and CXCL11/I-TAC, is restricted to Th1-promoting DC. In contrast, expression of Th2-associated chemokines does not strictly correlate with the Th2-promoting DC phenotype, except for CCL22/MDC, which is preferentially expressed by Th2-promoting DC. Because inflammatory chemokines and Th1-associated chemokines are constitutively expressed by mature Th1-promoting DC and CCL22/MDC is constitutively expressed by mature Th2-promoting DC, we propose a novel role for mature DC present in inflamed peripheral tissues in orchestrating the immune response by recruiting appropriate leucocyte populations to the site of pathogen entry.