title: Targeted delivery of lipid antigen to macrophages via the CD169/sialoadhesin endocytic pathway induces robust invariant natural killer T cell activation.
abstract: Invariant natural killer T (iNKT) cells induce a protective immune response triggered by foreign glycolipid antigens bound to CD1d on antigen-presenting cells (APCs). A limitation of using glycolipid antigens to stimulate immune responses in human patients has been the inability to target them to the most effective APCs. Recent studies have implicated phagocytic CD169(+) macrophages as major APCs in lymph nodes for priming iNKT cells in mice immunized with glycolipid antigen in particulate form. CD169 is known as sialoadhesin (Sn), a macrophage-specific adhesion and endocytic receptor of the siglec family that recognizes sialic acid containing glycans as ligands. We have recently developed liposomes decorated with glycan ligands for CD169/Sn suitable for targeted delivery to macrophages via CD169/Sn-mediated endocytosis. Here we show that targeted delivery of a lipid antigen to CD169(+) macrophages in vivo results in robust iNKT cell activation in liver and spleen using nanogram amounts of antigen. Activation of iNKT cells is abrogated in Cd169(-/-) mice and is macrophage-dependent, demonstrating that targeting CD169(+) macrophages is sufficient for systemic activation of iNKT cells. When pulsed with targeted liposomes, human monocyte-derived dendritic cells expressing CD169/Sn activated human iNKT cells, demonstrating the conservation of the CD169/Sn endocytic pathway capable of presenting lipid antigens to iNKT cells.
authors.affiliation: Department of Cell and Molecular Biology, and Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Norihito
authors.initials: N
authors.lastname: Kawasaki
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Vela
authors.forename: Corwin M
authors.initials: CM
authors.lastname: Nycholat
authors.forename: Christoph
authors.initials: C
authors.lastname: Rademacher
authors.forename: Archana
authors.initials: A
authors.lastname: Khurana
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Paul R
authors.initials: PR
authors.lastname: Crocker
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: James C
authors.initials: JC
authors.lastname: Paulson
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology; D004705:Endocytosis; D006017:Glycolipids / Q000276:immunology; D006801:Humans; D008024:Ligands; D008055:Lipids / Q000276:immunology*; D008081:Liposomes / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D055611:Natural Killer T-Cells / Q000166:cytology*; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000378:metabolism*
chemical_list: D000941:Antigens; D006017:Glycolipids; D008024:Ligands; D008055:Lipids; D008081:Liposomes; C571166:SIGLEC1 protein, human; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse
keywords: antigen delivery; antigen presentation; immune modulation