Toni M M van Capel

Publications of Toni M M van Capel

• 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.

• 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.

• 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.

• 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.

• 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.

• Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin.

  Authors: Hermelijn H Smits, Anneke Engering, Desiree van der Kleij, Esther C de Jong, Kim Schipper, Toni M M van Capel, Bas A J Zaat, Maria Yazdanbakhsh, Eddy A Wierenga, Yvette van Kooyk, Martien L Kapsenberg

  The Journal of allergy and clinical immunology. 07/2005; 115(6):1260-7.

  BACKGROUND: Lactobacilli are probiotic bacteria that are frequently tested in the management of allergic diseases or gastroenteritis. It is hypothesized that these probiotics have immunoregulatoryBACKGROUND: Lactobacilli are probiotic bacteria that are frequently tested in the management of allergic diseases or gastroenteritis. It is hypothesized that these probiotics have immunoregulatory properties and promote mucosal tolerance, which is in part mediated by regulatory T cells (Treg cells). On the basis of pathogenic or tissue-specific priming, dendritic cells (DC) acquire different T cell-instructive signals and drive the differentiation of naive T H cells into either T H 1, T H 2, or regulatory effector T cells. OBJECTIVE: We studied in what way different species of lactobacilli prime human DCs for their ability to drive Treg cells. METHODS: Human monocyte-derived DCs were cultured in vitro with lactobacilli of different species. RESULTS: Two different species of lactobacilli, Lactobacillus reuteri and Lactobacillus casei , but not Lactobacillus plantarum, prime monocyte-derived DCs to drive the development of Treg cells. These Treg cells produced increased levels of IL-10 and were capable of inhibiting the proliferation of bystander T cells in an IL-10-dependent fashion. Strikingly, both L reuteri and L casei , but not L plantarum , bind the C-type lectin DC-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN). Blocking antibodies to DC-SIGN inhibited the induction of the Treg cells by these probiotic bacteria, stressing that ligation of DC-SIGN can actively prime DCs to induce Treg cells. CONCLUSIONS: The targeting of DC-SIGN by certain probiotic bacteria might explain their beneficial effect in the treatment of a number of inflammatory diseases, including atopic dermatitis and Crohn's disease.

• Double-stranded RNA-exposed human keratinocytes promote Th1 responses by inducing a Type-1 polarized phenotype in dendritic cells: role of keratinocyte-derived tumor necrosis factor alpha, type I interferons, and interleukin-18.

  Authors: M Cristina Lebre, Jeanine C Antons, Pawel Kalinski, Joost H N Schuitemaker, Toni M M van Capel, Martien L Kapsenberg, Esther C de Jong

  The Journal of investigative dermatology. 07/2003; 120(6):990-7.

  Dendritic cells play a key role in establishing the class of immune response against invading pathogens. Upon engagement with double-stranded RNA, a major bioactive constituent of many virus types,Dendritic cells play a key role in establishing the class of immune response against invading pathogens. Upon engagement with double-stranded RNA, a major bioactive constituent of many virus types, immature dendritic cells develop into type 1 immunostimulatory dendritic cells that promote Th1 responses. Immature dendritic cells reside in the epithelia and are in close contact with keratinocytes. We studied to what extent dendritic cells can also adopt a type 1 immunostimulatory dendritic cell phenotype indirectly, as a result of the interaction with keratinocytes responding to double-stranded RNA. In contrast to supernatants from keratinocytes activated by the combination of tumor necrosis factor alpha and interleukin-1beta, supernatants from keratinocytes activated by synthetic double-stranded RNA, polyriboinosinic polyribocytidylic acid, comprised tumor necrosis factor alpha and type I interferons, which induced maturation of human monocyte-derived immature dendritic cells. In addition, dendritic cells matured in the presence of these supernatants strongly biased the development of Th1 cells from naive Th cells. This bias was dependent on keratinocyte-derived interferon-alpha/beta and interleukin-18, as neutralization of both interferon-alpha/beta and interleukin-18 in the keratinocyte culture supernatant reduced the development of interferon-gamma-producing Th cells. These findings suggest that keratinocytes can contribute to the development of selective Th1/Th2 responses through the induction of maturation and functional polarization of dendritic cells, indicating a novel role for keratinocytes as initiators and regulators of cutaneous T-cell-mediated inflammation. In addition, these results support the concept that, in addition to direct interaction with pathogens, dendritic cells may also be activated and primed by pathogen indirectly, via the effect of resident tissue cells responding to pathogen.

• Double-Stranded RNA-Exposed Human Keratinocytes Promote Th1 Responses by Inducing a Type-1 Polarized Phenotype in Dendritic Cells: Role of Keratinocyte-Derived Tumor Necrosis Factor α, Type I Interferons, and Interleukin-18

  Authors: M Cristina Lebre, Jeanine C Antons, Pawel Kalinski, Joost H N Schuitemaker, Toni M M van Capel, Martien L Kapsenberg, Esther C de Jong