title: Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16- Human Blood Monocytes in Serum-Free Condition.
abstract: Langerhans cells (LCs) are epithelial APCs that sense danger signals and in turn trigger specific immune responses. In steady-state, they participate in the maintenance of peripheral tolerance to self-antigens whereas under inflammation LCs efficiently trigger immune responses in secondary lymphoid organs. It has been demonstrated in mice that LC-deprived epithelia are rapidly replenished by short half-life langerin-expressing monocyte-derived LCs (MDLCs). These surrogate LCs are thought to be progressively replaced by langerin(high) LCs arising from self-renewing epithelial precursors of hematopoietic origin. How LCs arise from blood monocytes is not fully understood. Hence, we sought to characterize key factors that induce differentiation of langerin(high)-expressing monocyte-derived Langerhans-like cells. We identified GM-CSF and TGF-β1 as key cytokines to generate langerin(high)-expressing cells but only in serum-free conditions. These cells were shown to express the LC-specific TROP-2 and Axl surface markers and contained Birbeck granules. Surprisingly, E-cadherin was not spontaneously expressed by these cells but required a direct contact with keratinocytes to be stably induced. MDLCs induced stronger allogeneic T cell proliferations but released low amounts of inflammatory cytokines upon TLR stimulation compared with donor-paired monocyte-derived dendritic cells. Immature langerin(high) MDLCs were responsive to MIP-3β/CCL20 and CTAC/CCL27 chemokine stimulations. Finally, we demonstrated that those cells behaved as bona fide LCs when inserted in a three-dimensional rebuilt epithelium by becoming activated upon TLR or UV light stimulations. Collectively, these results prompt us to propose these langerin(high) MDLCs as a relevant model to address LC biology-related questions.
authors.affiliation: INSERM, UMR 1064, Center for Research in Transplantation and Immunology, 44093 Nantes, France; Institut de Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes, France; University of Nantes, 44093 Nantes, France; La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Gaëlle
authors.identifier: 0000-0001-7321-0373
authors.initials: G
authors.lastname: Picarda
authors.affiliation: INSERM, UMR 1064, Center for Research in Transplantation and Immunology, 44093 Nantes, France; Institut de Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes, France; University of Nantes, 44093 Nantes, France;
authors.forename: Coraline
authors.initials: C
authors.lastname: Chéneau
authors.affiliation: Institut de Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes, France;
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Humbert
authors.affiliation: INSERM, UMR 1064, Center for Research in Transplantation and Immunology, 44093 Nantes, France; Institut de Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes, France; University of Nantes, 44093 Nantes, France;
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bériou
authors.affiliation: University of Nantes, 44093 Nantes, France; INSERM, UMR 791, Laboratoire d'Ingénierie Ostéo-Articulaire et Dentaire, 44042 Nantes, France;
authors.forename: Paul
authors.initials: P
authors.lastname: Pilet
authors.affiliation: INSERM, UMR 1064, Center for Research in Transplantation and Immunology, 44093 Nantes, France; Institut de Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes, France; University of Nantes, 44093 Nantes, France;
authors.forename: Jérôme
authors.initials: J
authors.lastname: Martin
authors.affiliation: Department of Vascular and Plastic and Reconstructive Surgery, Nantes University Hospital, 44093 Nantes, France; and.
authors.forename: Franck
authors.initials: F
authors.lastname: Duteille
authors.affiliation: Department of Vascular and Plastic and Reconstructive Surgery, Nantes University Hospital, 44093 Nantes, France; and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Perrot
authors.affiliation: Department of Vascular and Plastic and Reconstructive Surgery, Nantes University Hospital, 44093 Nantes, France; and.
authors.forename: Frédérique
authors.identifier: 0000-0003-3500-2172
authors.initials: F
authors.lastname: Bellier-Waast
authors.affiliation: INSERM, UMR 1064, Center for Research in Transplantation and Immunology, 44093 Nantes, France; Institut de Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes, France; University of Nantes, 44093 Nantes, France;
authors.forename: Michèle
authors.initials: M
authors.lastname: Heslan
authors.affiliation: INSERM, UMR 1064, Center for Research in Transplantation and Immunology, 44093 Nantes, France; Institut de Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes, France; University of Nantes, 44093 Nantes, France;
authors.forename: Fabienne
authors.identifier: 0000-0003-0513-1387
authors.initials: F
authors.lastname: Haspot
authors.affiliation: Sterlab, 06220 Vallauris, France.
authors.forename: Fabien
authors.identifier: 0000-0001-7335-529X
authors.initials: F
authors.lastname: Guillon
authors.affiliation: INSERM, UMR 1064, Center for Research in Transplantation and Immunology, 44093 Nantes, France; Institut de Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes, France; University of Nantes, 44093 Nantes, France;
authors.forename: Regis
authors.identifier: 0000-0001-7900-7413
authors.initials: R
authors.lastname: Josien
authors.affiliation: INSERM, UMR 1064, Center for Research in Transplantation and Immunology, 44093 Nantes, France; Institut de Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes, France; University of Nantes, 44093 Nantes, France; franck.halary@univ-nantes.fr.
authors.forename: Franck Albert
authors.identifier: 0000-0003-0336-9615
authors.initials: FA
authors.lastname: Halary
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D001773:Blood Cells / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007519:Isoantigens / Q000276:immunology; D015603:Keratinocytes / Q000502:physiology*; D007801:Langerhans Cells / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008213:Lymphocyte Activation; D009000:Monocytes / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014466:Ultraviolet Rays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D007519:Isoantigens; D018950:Lipopolysaccharide Receptors; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; C499380:TACSTD2 protein, human; D053773:Transforming Growth Factor beta1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human