title: Targeted delivery of mycobacterial antigens to human dendritic cells via Siglec-7 induces robust T cell activation.
abstract: Lipids from mycobacteria can be presented to human T cells by group 1 CD1 Ag-presenting molecules (CD1a, CD1b, and CD1c). Group 1 CD1-restricted T cells are activated by lipid Ags presented by myeloid dendritic cells (DCs), after which they generate antibacterial effector functions, including IFN-γ secretion and cytolysis. Thus, mycobacterial lipids are being investigated as components of novel vaccines for mycobacterial infections. In this study we show that the mycobacterial lipid Ag C80 glucose-6-monomycolate can be delivered to human CD1b(+) DCs via targeted liposomal nanoparticles, leading to robust group 1 CD1-restricted activation of T cells. Targeting was achieved by decorating the liposomes with a high-affinity glycan ligand of sialic acid-binding Ig-like lectin (Siglec)-7, a siglec receptor expressed on DCs that mediates rapid endocytosis and transport of its cargo to lysosomes. An Ab to Siglec-7 completely blocked the binding of targeted liposomes to human monocyte-derived DCs (Mo-DCs), demonstrating their targeting specificity. Mo-DCs pulsed with targeted liposomes containing C80 glucose-6-monomycolate more potently activated a CD1b-restricted T cell line relative to Mo-DCs pulsed with free lipid Ag or antigenic liposomes without Siglec-7 ligand. These data suggest that the endocytic function of Siglec-7 can be exploited to deliver glycolipid Ags to their target cell and increase the efficiency of display to T cells.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Norihito
authors.initials: N
authors.lastname: Kawasaki
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Cory D
authors.initials: CD
authors.lastname: Rillahan
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Tan-Yun
authors.initials: TY
authors.lastname: Cheng
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Van Rhijn
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Macauley
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and.
authors.forename: D Branch
authors.initials: DB
authors.lastname: Moody
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; jpaulson@scripps.edu.
authors.forename: James C
authors.initials: JC
authors.lastname: Paulson
mesh_terms: D000906:Antibodies / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000276:immunology; D018949:Antigens, CD1 / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology*; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis / Q000276:immunology; D006017:Glycolipids / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D037102:Lectins / Q000276:immunology*; D008081:Liposomes / Q000008:administration & dosage / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008247:Lysosomes / Q000276:immunology; D009161:Mycobacterium / Q000276:immunology; D053758:Nanoparticles / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000906:Antibodies; D000942:Antigens, Bacterial; D018949:Antigens, CD1; D015214:Antigens, Differentiation, Myelomonocytic; C419394:CD1b antigen; D006017:Glycolipids; D037102:Lectins; D008081:Liposomes; C402206:SIGLEC7 protein, human; D032581:Tuberculosis Vaccines; C048938:glucose mycolate; D007371:Interferon-gamma