Imaging

@article{schaeffer_sp2-iminosugar_2019,

title = {sp2-Iminosugar glycolipids as inhibitors of lipopolysaccharide-mediated human dendritic cell activation in vitro and of acute inflammation in mice in vivo},

author = {Evelyne Schaeffer and Elena M Sánchez-Fernández and Rita Gonçalves-Pereira and Vincent Flacher and Delphine Lamon and Monique Duval and Jean-Daniel Fauny and José M García Fernández and Christopher G Mueller and Carmen Ortiz Mellet},

doi = {10.1016/j.ejmech.2019.02.078},

issn = {1768-3254},

year  = {2019},

date = {2019-05-01},

journal = {European Journal of Medicinal Chemistry},

volume = {169},

pages = {111--120},

abstract = {Glycolipid mimetics consisting of a bicyclic polyhydroxypiperidine-cyclic carbamate core and a pseudoanomeric hydrophobic tail, termed sp2-iminosugar glycolipids (sp2-IGLs), target microglia during neuroinflammatory processes. Here we have synthesized and investigated new variants of sp2-IGLs for their ability to suppress the activation of human monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS) signaling through Toll-like receptor 4. We report that the best lead was (1R)-1-dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin (DSO2-ONJ), able to inhibit LPS-induced TNFα production and maturation of DCs. Immunovisualization experiments, using a mannoside glycolipid conjugate (MGC) that also suppress LPS-mediated DC activation as control, evidenced a distinct mode of action for the sp2-IGLs: unlike MGCs, DSO2-ONJ did not elicit internalization of the LPS co-receptor CD14 or induce its co-localization with the Toll-like receptor 4. In a mouse model of LPS-induced acute inflammation, DSO2-ONJ demonstrated anti-inflammatory activity by inhibiting the production of the pro-inflammatory interleukin-6. The ensemble of the data highlights sp2-IGLs as a promising new class of molecules against inflammation by interfering in Toll-like receptor intracellular signaling.},

keywords = {Activation, Acute Disease, Animals, antagonists & inhibitors, CD14, Cells, chemical synthesis, Chemistry, CO-RECEPTOR, Cultured, Dendritic cell, Dendritic Cells, Dose-Response Relationship, Drug, drug effects, drug therapy, Glycolipid, Glycolipids, Human, Humans, Iminosugar, immunopathology, IN VITRO, In vivo, Inbred C57BL, inflammation, Interleukin-6, lipopolysaccharide, Lipopolysaccharides, LPS, Male, Maturation, metabolism, Mice, MICROGLIA, Molecular Structure, mouse, pathology, Pharmacology, PRODUCTION, Receptor, signaling, Structure-Activity Relationship, Sulfone, Sulfoxide, Tail, target, Team-Mueller},

pubstate = {published},

tppubtype = {article}

}

@article{schaeffer_inhibition_2018,

title = {Inhibition of dengue virus infection by mannoside glycolipid conjugates},

author = {Evelyne Schaeffer and Vincent Flacher and Patrick Neuberg and Astrid Hoste and Adrien Brulefert and Jean-Daniel Fauny and Alain Wagner and Christopher G Mueller},

doi = {10.1016/j.antiviral.2018.04.005},

issn = {1872-9096},

year  = {2018},

date = {2018-01-01},

journal = {Antiviral Research},

volume = {154},

pages = {116--123},

abstract = {Dengue virus (DENV), a mosquito-borne flavivirus, causes severe and potentially fatal symptoms in millions of infected individuals each year. Although dengue fever represents a major global public health problem, the vaccines or antiviral drugs proposed so far have not shown sufficient efficacy and safety, calling for new antiviral developments. Here we have shown that a mannoside glycolipid conjugate (MGC) bearing a trimannose head with a saturated lipid chain inhibited DENV productive infection. It showed remarkable cell promiscuity, being active in human skin dendritic cells, hepatoma cell lines and Vero cells, and was active against all four DENV serotypes, with an IC50 in the low micromolar range. Time-of-addition experiments and structure-activity analyses revealed the importance of the lipid chain to interfere with an early viral infection step. This, together with a correlation between antiviral activity and membrane polarization by the lipid moiety indicated that the inhibitor functions by blocking viral envelope fusion with the endosome membrane. These finding establish MGCs as a novel class of antivirals against the DENV.},

keywords = {Cell Membrane, Dendritic Cells, Dengue virus, I2CT, Imagerie, inhibitors, Macrophages, Skin, Team-Mueller},

pubstate = {published},

tppubtype = {article}

}

@article{schaeffer_inhibition_2018b,

title = {Inhibition of dengue virus infection by mannoside glycolipid conjugates},

author = {Evelyne Schaeffer and Vincent Flacher and Patrick Neuberg and Astrid Hoste and Adrien Brulefert and Jean-Daniel Fauny and Alain Wagner and Christopher G Mueller},

doi = {10.1016/j.antiviral.2018.04.005},

issn = {1872-9096},

year  = {2018},

date = {2018-01-01},

journal = {Antiviral Research},

volume = {154},

pages = {116--123},

abstract = {Dengue virus (DENV), a mosquito-borne flavivirus, causes severe and potentially fatal symptoms in millions of infected individuals each year. Although dengue fever represents a major global public health problem, the vaccines or antiviral drugs proposed so far have not shown sufficient efficacy and safety, calling for new antiviral developments. Here we have shown that a mannoside glycolipid conjugate (MGC) bearing a trimannose head with a saturated lipid chain inhibited DENV productive infection. It showed remarkable cell promiscuity, being active in human skin dendritic cells, hepatoma cell lines and Vero cells, and was active against all four DENV serotypes, with an IC50 in the low micromolar range. Time-of-addition experiments and structure-activity analyses revealed the importance of the lipid chain to interfere with an early viral infection step. This, together with a correlation between antiviral activity and membrane polarization by the lipid moiety indicated that the inhibitor functions by blocking viral envelope fusion with the endosome membrane. These finding establish MGCs as a novel class of antivirals against the DENV.},

keywords = {Animals, Antiviral Agents, Cell Line, Cell Membrane, Chemistry, Chlorocebus aethiops, Dendritic Cells, Dengue, Dengue virus, development, Drug, Drug Discovery, Flavivirus, function, Fusion, Glycolipids, Health, Hep G2 Cells, Human, Humans, immunopathology, infection, inhibition, inhibitors, Inhibitory Concentration 50, lipid, Macrophages, Mannosides, Membrane, Serogroup, Skin, Team-Mueller, vaccine, Vaccines, Vero Cells, viral Infection, virus, Virus Replication},

pubstate = {published},

tppubtype = {article}

}

@article{nehmar_therapeutic_2017,

title = {Therapeutic Modulation of Plasmacytoid Dendritic Cells in Experimental Arthritis},

author = {Ramzi Nehmar and Ghada Alsaleh and Benjamin Voisin and Vincent Flacher and Alexandre Mariotte and Victoria Saferding and Antonia Puchner and Birgit Niederreiter and Thierry Vandamme and Gernot Schabbauer and Philippe Kastner and Susan Chan and Peggy Kirstetter and Martin Holcmann and Christopher Mueller and Jean Sibilia and Seiamak Bahram and Stephan Blüml and Philippe Georgel},

doi = {10.1002/art.40225},

issn = {2326-5205},

year  = {2017},

date = {2017-01-01},

journal = {Arthritis & Rheumatology (Hoboken, N.J.)},

volume = {69},

number = {11},

pages = {2124--2135},

abstract = {OBJECTIVE: The role of plasmacytoid dendritic cells (PDCs) and type I interferons (IFNs) in rheumatoid arthritis (RA) remains a subject of controversy. This study was undertaken to explore the contribution of PDCs and type I IFNs to RA pathogenesis using various animal models of PDC depletion and to monitor the effect of localized PDC recruitment and activation on joint inflammation and bone damage. 

METHODS: Mice with K/BxN serum-induced arthritis, collagen-induced arthritis, and human tumor necrosis factor transgene insertion were studied. Symptoms were evaluated by visual scoring, quantification of paw swelling, determination of cytokine levels by enzyme-linked immunosorbent assay, and histologic analysis. Imiquimod-dependent therapeutic effects were monitored by transcriptome analysis (using quantitative reverse transcriptase-polymerase chain reaction) and flow cytometric analysis of the periarticular tissue. 

RESULTS: PDC-deficient mice showed exacerbation of inflammatory and arthritis symptoms after arthritogenic serum transfer. In contrast, enhancing PDC recruitment and activation to arthritic joints by topical application of the Toll-like receptor 7 (TLR-7) agonist imiquimod significantly ameliorated arthritis in various mouse models. Imiquimod induced an IFN signature and led to reduced infiltration of inflammatory cells. 

CONCLUSION: The therapeutic effects of imiquimod on joint inflammation and bone destruction are dependent on TLR-7 sensing by PDCs and type I IFN signaling. Our findings indicate that local recruitment and activation of PDCs represents an attractive therapeutic opportunity for RA patients.},

keywords = {Activation, Adjuvants, Aminoquinolines, Analysis, Animal, Animals, arthritis, Assay, cancer, Cells, cytokine, Cytokines, Dendritic Cells, DEPLETION, Disease Models, drug effects, Enzyme-Linked Immunosorbent Assay, Experimental, Flow Cytometry, Gene Expression Profiling, Genetics, GLYCOPROTEIN, Glycoproteins, Human, Humans, IFN, IKAROS, Ikaros Transcription Factor, imiquimod, Immunologic, Immunology, immunopathology, inflammation, interferon, Interferon Type I, interferons, Knockout, Membrane, Membrane Glycoproteins, METHOD, methods, Mice, MODULATION, mouse, Necrosis, NECROSIS-FACTOR-ALPHA, pathogenesis, Patients, Pharmacology, physiology, plasmacytoid dendritic cells, Protein, Receptor, Reverse Transcriptase Polymerase Chain Reaction, rheumatoid, rheumatoid arthritis, Serum, signaling, Team-Mueller, TLR7, Toll-Like Receptor 7, TOPICAL APPLICATION, Transcription, TRANSCRIPTION FACTOR, transcriptome, transgenic, tumor, Tumor Necrosis Factor, Tumor Necrosis Factor-alpha},

pubstate = {published},

tppubtype = {article}

}

@article{saliba_enhancing_2017,

title = {Enhancing tumor specific immune responses by transcutaneous vaccination},

author = {Hanadi Saliba and Béatrice Heurtault and Hasnaa Bouharoun-Tayoun and Vincent Flacher and Benoît Frisch and Sylvie Fournel and Soulaima Chamat},

doi = {10.1080/14760584.2017.1382357},

issn = {1744-8395},

year  = {2017},

date = {2017-01-01},

journal = {Expert Review of Vaccines},

volume = {16},

number = {11},

pages = {1079--1094},

abstract = {INTRODUCTION: Our understanding of the involvement of the immune system in cancer control has increased over recent years. However, the development of cancer vaccines intended to reverse tumor-induced immune tolerance remains slow as most current vaccine candidates exhibit limited clinical efficacy. The skin is particularly rich with multiple subsets of dendritic cells (DCs) that are involved to varying degrees in the induction of robust immune responses. Transcutaneous administration of cancer vaccines may therefore harness the immune potential of these DCs, however, this approach is hampered by the impermeability of the stratum corneum. Innovative vaccine formulations including various nanoparticles, such as liposomes, are therefore needed to properly deliver cancer vaccine components to skin DCs. Areas covered: The recent insights into skin DC subsets and their functional specialization, the potential of nanoparticle-based vaccines in transcutaneous cancer vaccination and, finally, the most relevant clinical trial advances in liposomal and in cutaneous cancer vaccines will be discussed. Expert commentary: To define the optimal conditions for mounting protective skin DC-induced anti-tumor immune responses, investigation of the cellular and molecular interplay that controls tumor progression should be pursued in parallel with clinical development. The resulting knowledge will then be translated into improved cancer vaccines that better target the most appropriate immune players.},

keywords = {Administration, Cancer vaccine, Cancer Vaccines, Clinical Trials as Topic, Cutaneous, Dendritic Cells, Humans, liposome, Liposomes, nanoparticle, Nanoparticles, Neoplasms, Skin, skin dendritic cell, Team-Mueller, transcutaneous vaccination, Treatment Outcome, Vaccination},

pubstate = {published},

tppubtype = {article}

}

@article{chypre_characterization_2016,

title = {Characterization and application of two RANK-specific antibodies with different biological activities},

author = {M Chypre and J Seaman and O G Cordeiro and L Willen and K A Knoop and A Buchanan and R C Sainson and I R Williams and H Yagita and P Schneider and C G Mueller},

doi = {10.1016/j.imlet.2016.01.003},

year  = {2016},

date = {2016-03-01},

journal = {Immunol.Lett.},

volume = {171},

number = {1879-0542 (Electronic)},

pages = {5--14},

abstract = {Antibodies play an important role in therapy and investigative biomedical research. The TNF-family member Receptor Activator of NF-kappaB (RANK) is known for its role in bone homeostasis and is increasingly recognized as a central player in immune regulation and epithelial cell activation. However, the study of RANK biology has been hampered by missing or insufficient characterization of high affinity tools that recognize RANK. Here, we present a careful description and comparison of two antibodies, RANK-02 obtained by phage display (Newa, 2014 [1]) and R12-31 generated by immunization (Kamijo, 2006 [2]). We found that both antibodies recognized mouse RANK with high affinity, while RANK-02 and R12-31 recognized human RANK with high and lower affinities, respectively. Using a cell apoptosis assay based on stimulation of a RANK:Fas fusion protein, and a cellular NF-kappaB signaling assay, we showed that R12-31 was agonist for both species. R12-31 interfered little or not at all with the binding of RANKL to RANK, in contrast to RANK-02 that efficiently prevented this interaction. Depending on the assay and species, RANK-02 was either a weak agonist or a partial antagonist of RANK. Both antibodies recognized human Langerhans cells, previously shown to express RANK, while dermal dendritic cells were poorly labeled. In vivo R12-31 agonist activity was demonstrated by its ability to induce the formation of intestinal villous microfold cells in mice. This characterization of two monoclonal antibodies should now allow better evaluation of their application as therapeutic reagents and investigative tools},

keywords = {Activation, Animals, ANTAGONIST, Antibodies, antibody, Antibody Affinity, Apoptosis, Assay, Cell Differentiation, Cell Surface Display Techniques, Cellular, Chemistry, comparison, Dendritic Cells, DERMAL DENDRITIC CELLS, Epithelial Cells, Epithelial microfold cell, Epitopes, Fusion, FUSION PROTEIN, HEK293 Cells, Homeostasis, Human, Humans, immune regulation, Immunization, Immunology, Immunomodulation, immunopathology, In vivo, Inbred C57BL, Intestines, Jurkat Cells, Langerhans cell, Langerhans Cells, Mice, Monoclonal, monoclonal antibody, MONOCLONAL-ANTIBODY, mouse, NF-kappa B, NF-kappaB, pathology, Protein, rank, RANK (TNFRSF11a), Receptor, Receptor Activator of Nuclear Factor-kappa B, Regulation, Secondary, Signal Transduction, signaling, Team-Mueller, therapy},

pubstate = {published},

tppubtype = {article}

}

@article{dietrich_interleukin-36_2016,

title = {Interleukin-36 potently stimulates human M2 macrophages, Langerhans cells and keratinocytes to produce pro-inflammatory cytokines},

author = {Damien Dietrich and Praxedis Martin and Vincent Flacher and Yu Sun and David Jarrossay and Nicolo Brembilla and Christopher Mueller and Heather A Arnett and Gaby Palmer and Jennifer Towne and Cem Gabay},

doi = {10.1016/j.cyto.2016.05.012},

issn = {1096-0023},

year  = {2016},

date = {2016-01-01},

journal = {Cytokine},

volume = {84},

pages = {88--98},

abstract = {Interleukin (IL)-36 cytokines belong to the IL-1 family and include three agonists, IL-36 α, β and γ and one inhibitor, IL-36 receptor antagonist (IL-36Ra). IL-36 and IL-1 (α and β) activate similar intracellular pathways via their related heterodimeric receptors, IL-36R/IL-1RAcP and IL-1R1/IL-1RAcP, respectively. However, excessive IL-36 versus IL-1 signaling induces different phenotypes in humans, which may be related to differential expression of their respective receptors. We examined the expression of IL-36R, IL-1R1 and IL-1RAcP mRNA in human peripheral blood, tonsil and skin immune cells by RT-qPCR. Monocyte-derived dendritic cells (MDDC), M0, M1 or M2-polarized macrophages, primary keratinocytes, dermal macrophages and Langerhans cells (LC) were stimulated with IL-1β or IL-36β. Cytokine production was assessed by RT-qPCR and immunoassays. The highest levels of IL-36R mRNA were found in skin-derived keratinocytes, LC, dermal macrophages and dermal CD1a(+) DC. In the blood and in tonsils, IL-36R mRNA was predominantly found in myeloid cells. By contrast, IL-1R1 mRNA was detected in almost all cell types with higher levels in tonsil and skin compared to peripheral blood immune cells. IL-36β was as potent as IL-1β in stimulating M2 macrophages, keratinocytes and LC, less potent than IL-1β in stimulating M0 macrophages and MDDC, and exerted no effects in M1 and dermal macrophages. Levels of IL-1Ra diminished the ability of M2 macrophages to respond to IL-1. Taken together, these data are consistent with the association of excessive IL-36 signaling with an inflammatory skin phenotype and identify human LC and M2 macrophages as new IL-36 target cells.},

keywords = {agonists, ANTAGONIST, BLOOD, Cells, Cellular, Chemistry, Cultured, cytokine, CYTOKINE PRODUCTION, Cytokines, Dendritic Cells, DERMATOLOGY, Expression, Human, Humans, IL-1, IL-1R1, IL-1ra, IL-36, IL-36R, Immunoassay, Immunology, immunopathology, inflammation, Interleukin, Interleukin-1 Receptor Accessory Protein, Interleukin-1 Type I, KERATINOCYTES, Langerhans Cells, Macrophage, Macrophages, messenger, Molecular Biology, Monocytes, mRNA, Myeloid Cells, pathology, Phenotype, PRODUCTION, PROINFLAMMATORY CYTOKINES, Receptor, receptor antagonist, Receptors, RNA, signaling, Skin, target, Team-Mueller, TONSIL},

pubstate = {published},

tppubtype = {article}

}

@article{flacher_mannoside_2015b,

title = {Mannoside Glycolipid Conjugates Display Anti-inflammatory Activity by Inhibition of Toll-like Receptor-4 Mediated Cell Activation},

author = {Vincent Flacher and Patrick Neuberg and Floriane Point and François Daubeuf and Quentin Muller and David Sigwalt and Jean-Daniel Fauny and Jean-Serge Remy and Nelly Frossard and Alain Wagner and Christopher G Mueller and Evelyne Schaeffer},

doi = {10.1021/acschembio.5b00552},

issn = {1554-8937},

year  = {2015},

date = {2015-12-01},

journal = {ACS chemical biology},

volume = {10},

number = {12},

pages = {2697--2705},

abstract = {Inhibition of excessive Toll-like receptor 4 (TLR4) signaling is a therapeutic approach pursued for many inflammatory diseases. We report that Mannoside Glycolipid Conjugates (MGCs) selectively blocked TLR4-mediated activation of human monocytes and monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS). They potently suppressed pro-inflammatory cytokine secretion and maturation of DCs exposed to LPS, leading to impaired T cell stimulation. MGCs did not interfere with LPS and could act in a delayed manner, hours after LPS stimulation. Their inhibitory action required both the sugar heads and the lipid chain, although the nature of the sugar and the structure of the lipid tail could be modified. They blocked early signaling events at the cell membrane, enhanced internalization of CD14 receptors, and prevented colocalization of CD14 and TLR4, thereby abolishing NF-κB nuclear translocation. When the best lead conjugate was tested in a mouse model of LPS-induced acute lung inflammation, it displayed an anti-inflammatory action by suppressing the recruitment of neutrophils. Thus, MGCs could serve as promising leads for the development of selective TLR4 antagonistic agents for inflammatory diseases.},

keywords = {Activation, Animals, Anti-Inflammatory Agents, Carbohydrate Sequence, CD14, Cell Membrane, Cells, Chemistry, Cultured, cytokine, Dendritic Cells, development, disease, Glycolipids, Human, Humans, immunopathology, Inbred BALB C, inflammation, inhibition, lipid, lipopolysaccharide, Lipopolysaccharides, LPS, LUNG, Mannosides, Maturation, Membrane, Mice, monocyte, Monocytes, mouse, neutrophils, NF-kappaB, Pneumonia, Protein-Serine-Threonine Kinases, Receptor, secretion, signaling, Structure-Activity Relationship, Tail, Team-Mueller, TLR4, Toll-Like Receptor 4},

pubstate = {published},

tppubtype = {article}

}

@article{haid_langerhans_2015,

title = {Langerhans cells in the sebaceous gland of the murine skin},

author = {Bernhard Haid and David E Schlögl and Martin Hermann and Christoph H Tripp and Patrizia Stoitzner and Nikolaus Romani and Vincent Flacher},

doi = {10.1111/exd.12803},

issn = {1600-0625},

year  = {2015},

date = {2015-11-01},

journal = {Experimental Dermatology},

volume = {24},

number = {11},

pages = {899--901},

keywords = {Animals, Dendritic Cells, DERMATOLOGY, DERMIS, Epidermis, Inbred BALB C, Inbred C57BL, Langerhans Cells, Langerin, Letter, Mice, murine, pilosebaceous unit, sebaceous gland, Sebaceous Glands, Skin, Team-Mueller},

pubstate = {published},

tppubtype = {article}

}

@article{schaeffer_dermal_2015b,

title = {Dermal CD14(+) Dendritic Cell and Macrophage Infection by Dengue Virus Is Stimulated by Interleukin-4},

author = {Evelyne Schaeffer and Vincent Flacher and Vasiliki Papageorgiou and Marion Decossas and Jean-Daniel Fauny and Melanie Krämer and Christopher G Mueller},

doi = {10.1038/jid.2014.525},

issn = {1523-1747},

year  = {2015},

date = {2015-07-01},

journal = {The Journal of Investigative Dermatology},

volume = {135},

number = {7},

pages = {1743--1751},

abstract = {Dengue virus (DENV) is responsible for the most prevalent arthropod-borne viral infection in humans. Events decisive for disease development occur in the skin after virus inoculation by the mosquito. Yet, the role of human dermis-resident immune cells in dengue infection and disease remains elusive. Here we investigated how dermal dendritic cells (dDCs) and macrophages (dMs) react to DENV and impact on immunopathology. We show that both CD1c(+) and CD14(+) dDC subsets were infected, but viral load greatly increased in CD14(+) dDCs upon IL-4 stimulation, which correlated with upregulation of virus-binding lectins Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin (DC-SIGN/CD209) and mannose receptor (CD206). IL-4 also enhanced T-cell activation by dDCs, which was further increased upon dengue infection. dMs purified from digested dermis were initially poorly infected but actively replicated the virus and produced TNF-α upon lectin upregulation in response to IL-4. DC-SIGN(+) cells are abundant in inflammatory skin with scabies infection or Th2-type dermatitis, suggesting that skin reactions to mosquito bites heighten the risk of infection and subsequent immunopathology. Our data identify dDCs and dMs as primary arbovirus target cells in humans and suggest that dDCs initiate a potent virus-directed T-cell response, whereas dMs fuel the inflammatory cascade characteristic of dengue fever.},

keywords = {Abdominal Wall, Activation, Adhesion, adhesion molecules, Antigen-Presenting Cells, arbovirus, C-Type, Cell Adhesion, Cell Adhesion Molecules, Cell Surface, Cells, Chemistry, Confocal, Cultured, cytokine, Cytokines, cytology, Dendritic Cells, Dengue, Dengue virus, DERMAL DENDRITIC CELLS, Dermatitis, DERMIS, development, disease, Enzyme-Linked Immunosorbent Assay, Epidermal Cells, Epidermis, Human, Humans, ICAM-3, IL-4, Immunology, immunopathology, infection, Interleukin-4, Langerhans Cells, LECTIN, Lectins, Lymphocyte Activation, Macrophage, Macrophages, metabolism, Microscopy, pathogenicity, physiopathology, Receptor, Receptors, Scabies, Sensitivity and Specificity, Skin, Skin Diseases, SUBSETS, T CELL ACTIVATION, target, Team-Mueller, TNF ALPHA, Viral, viral Infection, Viral Load, virology, virus},

pubstate = {published},

tppubtype = {article}

}

@article{flacher_murine_2014,

title = {Murine Langerin+ dermal dendritic cells prime CD8+ Ŧ cells while Langerhans cells induce cross-tolerance},

author = {Vincent Flacher and Christoph H Tripp and David G Mairhofer and Ralph M Steinman and Patrizia Stoitzner and Juliana Idoyaga and Nikolaus Romani},

doi = {10.15252/emmm.201303283},

issn = {1757-4684},

year  = {2014},

date = {2014-09-01},

journal = {EMBO molecular medicine},

volume = {6},

number = {9},

pages = {1191--1204},

abstract = {Skin dendritic cells (DCs) control the immunogenicity of cutaneously administered vaccines. Antigens targeted to DCs via the C-type lectin Langerin/CD207 are cross-presented to CD8(+) T cells in vivo. We investigated the relative roles of Langerhans cells (LCs) and Langerin(+) dermal DCs (dDCs) in different vaccination settings. Poly(I:C) and anti-CD40 agonist antibody promoted cytotoxic responses upon intradermal immunization with ovalbumin (OVA)-coupled anti-Langerin antibodies (Langerin/OVA). This correlated with CD70 upregulation in Langerin(+) dDCs, but not LCs. In chimeric mice where Langerin targeting was restricted to dDCs, CD8(+) T-cell memory was enhanced. Conversely, providing Langerin/OVA exclusively to LCs failed to prime cytotoxicity, despite initial antigen cross-presentation to CD8(+) T cells. Langerin/OVA combined with imiquimod could not prime CD8(+) T cells and resulted in poor cytotoxicity in subsequent responses. This tolerance induction required targeting and maturation of LCs. Altogether, Langerin(+) dDCs prime long-lasting cytotoxic responses, while cross-presentation by LCs negatively influences CD8(+) T-cell priming. Moreover, this highlights that DCs exposed to TLR agonists can still induce tolerance and supports the existence of qualitatively different DC maturation programs.},

keywords = {agonists, Animals, Antibodies, antibody, Antigen, Antigen Presentation, Antigens, C-Type, C-type lectin, cancer, CD70, CD8-Positive T-Lymphocytes, CD8+ T cells, CD8+ T‐cell responses, Cellular, CROSS-PRESENTATION, Cross-Priming, Cytotoxicity, Dendritic Cells, DERMAL DENDRITIC CELLS, DERMATOLOGY, disease, imiquimod, Immunization, IMMUNOGENICITY, Immunologic Memory, Immunological, Immunology, In vivo, Inbred C57BL, INDUCTION, Intradermal, Langerhans Cells, LECTIN, Lectins, Mannose-Binding Lectins, Maturation, Mice, Models, murine, OVALBUMIN, physiology, priming, RESPONSES, Skin, Surface, T CELLS, T-CELLS, Team-Mueller, tolerance, Vaccination, vaccine, Vaccines},

pubstate = {published},

tppubtype = {article}

}

@article{voisin_anatomical_2014,

title = {Anatomical distribution analysis reveals lack of Langerin+ dermal dendritic cells in footpads and tail of C57BL/6 mice},

author = {Benjamin Voisin and David Gabriel Mairhofer and Suzie Chen and Patrizia Stoitzner and Christopher George Mueller and Vincent Flacher},

doi = {10.1111/exd.12373},

issn = {1600-0625},

year  = {2014},

date = {2014-01-01},

journal = {Experimental Dermatology},

volume = {23},

number = {5},

pages = {354--356},

abstract = {Epidermal Langerhans cells (LCs) and dermal dendritic cells (dDCs) capture cutaneous antigens and present them to T-cells in lymph nodes (LNs). The function of LCs and Langerin+ dDCs was extensively studied in the mouse, but their anatomical repartition is unknown. Here, we found LCs in back skin, footpads and tail skin of C57BL/6, BALB/c, 129/Sv and CBA/J mice. Langerin+ dDCs were readily observed in back skin of all strains, but only in footpads and tail of BALB/c and CBA/J mice. Similarly, while LCs were equally present in all LNs and strains, Langerin+ dDCs were found in popliteal LNs (draining footpads) only in BALB/c and CBA/J mice. The sciatic LNs, which we identified as the major tail-draining lymphoid organ, were devoid of Langerin+ dDCs in all strains. Thus, functionally different DCs reside in different skin areas, with variations among mouse strains, implying a potential impact on the cutaneous immune reaction.},

keywords = {Analysis, Animals, Antigen, Antigens, C-Type, CD, CD11c Antigen, Cell Adhesion Molecules, Dendritic Cells, DERMAL DENDRITIC CELLS, Epithelial Cell Adhesion Molecule, footpad skin, function, Hindlimb, immunopathology, Inbred BALB C, Inbred C57BL, Inbred CBA, inflammation, Integrin alpha Chains, Langerhans Cells, Lectins, Letter, Leukocyte Common Antigens, LYMPH, LYMPH NODE, Lymph Nodes, Mannose-Binding Lectins, Mice, mouse, Neoplasm, Skin, skin-draining lymph nodes, Surface, T CELLS, T-CELLS, Tail, tail skin, Team-Mueller},

pubstate = {published},

tppubtype = {article}

}

@article{schaeffer_dynamic_2013,

title = {Dynamic micelles of mannoside glycolipids are more efficient than polymers for inhibiting HIV-1 trans-infection},

author = {Evelyne Schaeffer and Laure Dehuyser and David Sigwalt and Vincent Flacher and Serena Bernacchi and Olivier Chaloin and Jean-Serge Remy and Christopher G Mueller and Rachid Baati and Alain Wagner},

doi = {10.1021/bc4000806},

issn = {1520-4812},

year  = {2013},

date = {2013-11-01},

journal = {Bioconjugate Chemistry},

volume = {24},

number = {11},

pages = {1813--1823},

abstract = {Mannoside glycolipid conjugates are able to inhibit human immunodeficiency virus type 1 (HIV-1) trans-infection mediated by human dendritic cells (DCs). The conjugates are formed by three building blocks: a linear or branched mannose head, a hydrophilic linker, and a 24-carbon lipid chain. We have shown that, even as single molecules, these compounds efficiently target mannose-binding lectins, such as DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN) important for HIV-1 transmission. With the goal to optimize their inhibitory activity by supramolecular structure formation, we have compared saturated and unsaturated conjugates, as single molecules, self-assemblies of dynamic micelles, and photopolymerized cross-linked polymers. Surface plasmon resonance showed that, unexpectedly, polymers of trivalent conjugates did not display a higher binding affinity for DC-SIGN than single molecules. Interactions on a chip or in solution were independent of calcium; however, binding to DCs was inhibited by a calcium chelator. Moreover, HIV-1 trans-infection was mostly inhibited by dynamic micelles and not by rigid polymers. The inhibition data revealed a clear correlation between the structure and molecular assembly of a conjugate and its biological antiviral activity. We present an interaction model between DC-SIGN and conjugates-either single molecules, micelles, or polymers-that highlights that the most effective interactions by dynamic micelles involve both mannose heads and lipid chains. Our data reveal that trivalent glycolipid conjugates display the highest microbicide potential for HIV prophylaxis, as dynamic micelles conjugates and not as rigid polymers.},

keywords = {Anti-HIV Agents, Calcium, Cells, Chemistry, Cultured, Dendritic Cells, Dose-Response Relationship, Drug, Electron, fluorescence, Glycolipids, HIV, HIV Infections, HIV-1, Human, Humans, immunodeficiency, immunopathology, inhibition, LECTIN, Lectins, lipid, Mannosides, Micelles, Microbial Sensitivity Tests, Microscopy, Models, Molecular, Molecular Structure, Polymers, prophylaxis, Spectrometry, Structure-Activity Relationship, Surface Plasmon Resonance, target, Team-Mueller, Thermodynamics, Transmission, virus},

pubstate = {published},

tppubtype = {article}

}