title: Adaptor protein-3 in dendritic cells facilitates phagosomal toll-like receptor signaling and antigen presentation to CD4(+) T cells.
abstract: Effective major histocompatibility complex-II (MHC-II) antigen presentation from phagocytosed particles requires phagosome-intrinsic Toll-like receptor (TLR) signaling, but the molecular mechanisms underlying TLR delivery to phagosomes and how signaling regulates antigen presentation are incompletely understood. We show a requirement in dendritic cells (DCs) for adaptor protein-3 (AP-3) in efficient TLR recruitment to phagosomes and MHC-II presentation of antigens internalized by phagocytosis but not receptor-mediated endocytosis. DCs from AP-3-deficient pearl mice elicited impaired CD4(+) T cell activation and Th1 effector cell function to particulate antigen in vitro and to recombinant Listeria monocytogenes infection in vivo. Whereas phagolysosome maturation and peptide:MHC-II complex assembly proceeded normally in pearl DCs, peptide:MHC-II export to the cell surface was impeded. This correlated with reduced TLR4 recruitment and proinflammatory signaling from phagosomes by particulate TLR ligands. We propose that AP-3-dependent TLR delivery from endosomes to phagosomes and subsequent signaling mobilize peptide:MHC-II export from intracellular stores.
authors.affiliation: Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Adriana R
authors.initials: AR
authors.lastname: Mantegazza
authors.forename: Susan H
authors.initials: SH
authors.lastname: Guttentag
authors.forename: Jamel
authors.initials: J
authors.lastname: El-Benna
authors.forename: Miwa
authors.initials: M
authors.lastname: Sasai
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwasaki
authors.forename: Hao
authors.initials: H
authors.lastname: Shen
authors.forename: Terri M
authors.initials: TM
authors.lastname: Laufer
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marks
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D010588:Phagosomes / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
chemical_list: D033963:Adaptor Protein Complex 3; D000941:Antigens; D000949:Histocompatibility Antigens Class II; D008024:Ligands; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010455:Peptides; D051193:Toll-Like Receptors; D010047:Ovalbumin