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Chikungunya Virus Envelope Protein E2 Provides a Vector for Targeted Antigen Delivery to Human Dermal CD14+ Dendritic Cells

  • Adrien Brulefert
    Affiliations
    Laboratory CNRS I2CT/UPR3572 Immunology, Immunopathology and Therapeutic Chemistry, Drug Discovery and Development Institute (IMS), Institut de Biologie Moléculaire et Cellulaire, University of Strasbourg, Strasbourg, France
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  • Melanie Kraemer
    Affiliations
    Laboratory CNRS I2CT/UPR3572 Immunology, Immunopathology and Therapeutic Chemistry, Drug Discovery and Development Institute (IMS), Institut de Biologie Moléculaire et Cellulaire, University of Strasbourg, Strasbourg, France
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  • Marie Cumin
    Affiliations
    Laboratory CNRS I2CT/UPR3572 Immunology, Immunopathology and Therapeutic Chemistry, Drug Discovery and Development Institute (IMS), Institut de Biologie Moléculaire et Cellulaire, University of Strasbourg, Strasbourg, France
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  • Amandine Selle
    Affiliations
    Laboratory CNRS I2CT/UPR3572 Immunology, Immunopathology and Therapeutic Chemistry, Drug Discovery and Development Institute (IMS), Institut de Biologie Moléculaire et Cellulaire, University of Strasbourg, Strasbourg, France
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  • Astrid Hoste
    Affiliations
    Laboratory CNRS I2CT/UPR3572 Immunology, Immunopathology and Therapeutic Chemistry, Drug Discovery and Development Institute (IMS), Institut de Biologie Moléculaire et Cellulaire, University of Strasbourg, Strasbourg, France
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  • Hans-Henrik Gad
    Affiliations
    Unité Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, Paris, France
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  • Julia Rühl
    Affiliations
    Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
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  • Jean-Baptiste Madinier
    Affiliations
    Laboratory CNRS I2CT/UPR3572 Immunology, Immunopathology and Therapeutic Chemistry, Drug Discovery and Development Institute (IMS), Institut de Biologie Moléculaire et Cellulaire, University of Strasbourg, Strasbourg, France
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  • Olivier Chaloin
    Affiliations
    Laboratory CNRS I2CT/UPR3572 Immunology, Immunopathology and Therapeutic Chemistry, Drug Discovery and Development Institute (IMS), Institut de Biologie Moléculaire et Cellulaire, University of Strasbourg, Strasbourg, France
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  • Christian Münz
    Affiliations
    Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
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  • Philippe Desprès
    Affiliations
    Unité Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, Paris, France

    Unité Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, Université de La Réunion, INSERM U1187, CNRS UMR 9192, IRD UMR 249, Sainte-Clotilde, La Réunion, France
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  • Christopher George Mueller
    Affiliations
    Laboratory CNRS I2CT/UPR3572 Immunology, Immunopathology and Therapeutic Chemistry, Drug Discovery and Development Institute (IMS), Institut de Biologie Moléculaire et Cellulaire, University of Strasbourg, Strasbourg, France
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  • Vincent Flacher
    Correspondence
    Corresponding author
    Affiliations
    Laboratory CNRS I2CT/UPR3572 Immunology, Immunopathology and Therapeutic Chemistry, Drug Discovery and Development Institute (IMS), Institut de Biologie Moléculaire et Cellulaire, University of Strasbourg, Strasbourg, France
    Search for articles by this author
      Therapeutic modulation of human cutaneous antigen-presenting cells (APCs) that control the fate of T cells represents an interesting option for immunotherapy. Because they capture glycosylated proteins by C-type lectins, lectin-targeting antibodies have been used to specifically convey antigens to APCs (
      • Kastenmüller W.
      • Kastenmüller K.
      • Kurts C.
      • Seder R.A.
      Dendritic cell-targeted vaccines—hope or hype?.
      ;
      • Romani N.
      • Flacher V.
      • Tripp C.H.
      • Sparber F.
      • Ebner S.
      • Stoitzner P.
      Targeting skin dendritic cells to improve intradermal vaccination.
      ;
      • Stoitzner P.
      • Schaffenrath S.
      • Tripp C.H.
      • Reider D.
      • Komenda K.
      • Del Frari B.
      • et al.
      Human skin dendritic cells can be targeted in situ by intradermal injection of antibodies against lectin receptors.
      ). Beyond the potential therapeutic applications, APC-targeting strategies can be harnessed to acquire fundamental knowledge about their function (
      • Flacher V.
      • Tripp C.H.
      • Mairhofer D.G.
      • Steinman R.M.
      • Stoitzner P.
      • Idoyaga J.
      • et al.
      Murine Langerin+ dermal dendritic cells prime CD8+ T cells while Langerhans cells induce cross-tolerance [published correction appears in EMBO Mol Med 2014;6:1638].
      ). In human skin, epidermal Langerhans cells, CD1c+ dermal conventional type-2 dendritic cells (DCs), and CD141+ dermal conventional type-1 DCs (
      • Nestle F.O.
      • Di Meglio P.
      • Qin J.Z.
      • Nickoloff B.J.
      Skin immune sentinels in health and disease.
      ;
      • Schlitzer A.
      • McGovern N.
      • Ginhoux F.
      Dendritic cells and monocyte-derived cells: two complementary and integrated functional systems.
      ) can migrate to lymph nodes and stimulate T cells. Dermal APCs (dAPCs) include two CD14+ subsets that express the lectins Mannose Receptor/CD206 and DC-SIGN/CD209 (
      • Klechevsky E.
      • Morita R.
      • Liu M.
      • Cao Y.
      • Coquery S.
      • Thompson-Snipes L.
      • et al.
      Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells.
      ;
      • McGovern N.
      • Schlitzer A.
      • Gunawan M.
      • Jardine L.
      • Shin A.
      • Poyner E.
      • et al.
      Human dermal CD14+ cells are a transient population of monocyte-derived macrophages [published correction appears in Immunity 2015;42:391].
      ). During skin explant culture, CD14+ dermal DCs (dDCs) migrate into the supernatant, whereas sessile dermal macrophages require enzymatic digestion to be isolated. Still, CD14+ dDCs and dermal macrophages display strong similarities (
      • McGovern N.
      • Schlitzer A.
      • Gunawan M.
      • Jardine L.
      • Shin A.
      • Poyner E.
      • et al.
      Human dermal CD14+ cells are a transient population of monocyte-derived macrophages [published correction appears in Immunity 2015;42:391].
      ). They are both considered permanent dermal residents that exert local functions in pathogen capture (e.g., arthropod-borne viruses) (
      • Kwan W.H.
      • Navarro-Sanchez E.
      • Dumortier H.
      • Decossas M.
      • Vachon H.
      • dos Santos F.B.
      • et al.
      Dermal-type macrophages expressing CD209/DC-SIGN show inherent resistance to dengue virus growth.
      ;
      • Schaeffer E.
      • Flacher V.
      • Papageorgiou V.
      • Decossas M.
      • Fauny J.D.
      • Krämer M.
      • et al.
      Dermal CD14(+) dendritic cell and macrophage infection by dengue virus is stimulated by interleukin-4.
      ) and may interact with skin-resident memory T cells (
      • Clark R.A.
      Resident memory T cells in human health and disease.
      ). Subset differences might reflect their origin, that is, monocyte-derived dDCs versus embryonically seeded resident macrophages (
      • Ginhoux F.
      • Guilliams M.
      Tissue-resident macrophage ontogeny and homeostasis.
      ;
      • McGovern N.
      • Schlitzer A.
      • Gunawan M.
      • Jardine L.
      • Shin A.
      • Poyner E.
      • et al.
      Human dermal CD14+ cells are a transient population of monocyte-derived macrophages [published correction appears in Immunity 2015;42:391].
      ). Because tools to specifically target CD14+ dAPCs remain scarce (
      • Duinkerken S.
      • Horrevorts S.K.
      • Kalay H.
      • Ambrosini M.
      • Rutte L.
      • De Gruijl T.D.
      • et al.
      Glyco-dendrimers as intradermal anti-tumor vaccine targeting multiple skin DC subsets.
      ), we propose in this study a previously unreported approach on the basis of recombinant arboviral envelope proteins.

      Abbreviations:

      APC (antigen-presenting cell), CHIK (Chikungunya), CHIKV (Chikungunya virus), dAPC (dermal antigen-presenting cell), DC (dendritic cell), dDC (dermal dendritic cell), MDDC (monocyte-derived dendritic cell), MDdM (monocyte-derived dermal-like macrophage)
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