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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Protein Complex 3 / immunology*
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Adaptor Protein Complex 3 / metabolism
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Animals
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Antigen Presentation / immunology*
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Antigens / immunology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation / immunology
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Cells, Cultured
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Endocytosis / immunology
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Histocompatibility Antigens Class II / immunology
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Histocompatibility Antigens Class II / metabolism
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Ligands
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Listeria monocytogenes / immunology
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Listeriosis / immunology
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Listeriosis / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Myeloid Differentiation Factor 88 / immunology
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Myeloid Differentiation Factor 88 / metabolism
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Ovalbumin / immunology
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Ovalbumin / metabolism
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Peptides / immunology
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Peptides / metabolism
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Phagocytosis / immunology
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Phagosomes / immunology*
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Phagosomes / metabolism
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Signal Transduction / immunology
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Toll-Like Receptors / immunology*
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Toll-Like Receptors / metabolism
Substances
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Adaptor Protein Complex 3
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Antigens
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Histocompatibility Antigens Class II
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Ligands
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Peptides
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Toll-Like Receptors
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Ovalbumin