title: Langerin-mediated internalization of a modified peptide routes antigens to early endosomes and enhances cross-presentation by human Langerhans cells.
abstract: The potential of the skin immune system to generate immune responses is well established, and the skin is actively exploited as a vaccination site. Human skin contains several antigen-presenting cell subsets with specialized functions. In particular, the capacity to cross-present exogenous antigens to CD8+ T cells is of interest for the design of effective immunotherapies against viruses or cancer. Here, we show that primary human Langerhans cells (LCs) were able to cross-present a synthetic long peptide (SLP) to CD8+T cells. In addition, modification of this SLP using antibodies against the receptor langerin, but not dectin-1, further enhanced the cross-presenting capacity of LCs through routing of internalized antigens to less proteolytic early endosome antigen 1+early endosomes. The potency of LCs to enhance CD8+T-cell responses could be further increased through activation of LCs with the toll-like receptor 3 ligand polyinosinic:polycytidylic acid (pI:C). Altogether, the data provide evidence that human LCs are able to cross-present antigens after langerin-mediated internalization. Furthermore, the potential for antigen modification to target LCs specifically provides a rationale for generating effective anti-tumor or anti-viral cytotoxic T lymphocyte responses.
authors.affiliation: Department of Molecular Cell Biology and Immunology,VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Fehres
authors.affiliation: Department of Molecular Cell Biology and Immunology,VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Duinkerken
authors.affiliation: Department of Molecular Cell Biology and Immunology,VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Sven Cm
authors.initials: SC
authors.lastname: Bruijns
authors.affiliation: Department of Molecular Cell Biology and Immunology,VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Hakan
authors.initials: H
authors.lastname: Kalay
authors.affiliation: Department of Molecular Cell Biology and Immunology,VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: van Vliet
authors.affiliation: Department of Molecular Cell Biology and Immunology,VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Martino
authors.initials: M
authors.lastname: Ambrosini
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
authors.affiliation: Department of Molecular Cell Biology and Immunology,VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Wendy Wj
authors.initials: WW
authors.lastname: Unger
authors.affiliation: Department of Molecular Cell Biology and Immunology,VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Garcia-Vallejo
authors.affiliation: Department of Molecular Cell Biology and Immunology,VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
mesh_terms: D000906:Antibodies / Q000378:metabolism; D000941:Antigens / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism*; D002451:Cell Compartmentation; D002454:Cell Differentiation / Q000187:drug effects; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology*; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007801:Langerhans Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism*; D008024:Ligands; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D012867:Skin / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D000906:Antibodies; D000941:Antigens; D015703:Antigens, CD; D037181:Lectins, C-Type; D008024:Ligands; D037241:Mannose-Binding Lectins; D010455:Peptides; D011070:Poly I-C; D051193:Toll-Like Receptors; D000099181:Dectin-1; C121916:CD207 protein, human