Abstract
Antiviral or antitumor immunity requires activation of cytotoxic CD8+ T cells by dendritic cells, which present viral or tumor antigens on major histocompatibility complex (MHC) class I molecules. The intracellular mechanisms facilitating MHC class I-restricted presentation of extracellular antigens ('cross-presentation') are unclear. Here we demonstrate that cross-presentation of soluble antigen occurred in an early endosomal compartment distinct from the endoplasmic reticulum where endogenous antigen is loaded onto MHC class I. Efficient cross-presentation required endotoxin-induced, Toll-like receptor 4- and signaling molecule MyD88-dependent relocation of the transporter associated with antigen processing, essential for loading of MHC class I, to early endosomes. Transport of cross-presented antigen from endosomes to the cell surface was inhibited by primaquine, which blocks endosomal trafficking. Thus, cross-presentation is spatially and mechanistically separated from endogenous MHC class I-restricted antigen presentation and is biased toward antigens containing microbial molecular patterns.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / chemistry
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ATP-Binding Cassette Transporters / immunology
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Antigen Presentation
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Antigens / immunology
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Antigens / metabolism
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Cross-Priming
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Endosomes / metabolism
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Histocompatibility Antigens Class I / immunology*
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Histocompatibility Antigens Class I / metabolism
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Lectins, C-Type / deficiency
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Lectins, C-Type / genetics
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Mannose Receptor
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Mannose-Binding Lectins / deficiency
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Mannose-Binding Lectins / genetics
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Mice
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Mice, Knockout
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Myeloid Differentiation Factor 88 / immunology
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Ovalbumin / immunology
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Ovalbumin / metabolism
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Primaquine / pharmacology
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Protein Subunits / immunology
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Protein Transport / drug effects
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / genetics
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Solubility
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T-Lymphocytes, Cytotoxic / immunology
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Toll-Like Receptor 4 / immunology
Substances
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ATP-Binding Cassette Transporters
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Antigens
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Histocompatibility Antigens Class I
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Lectins, C-Type
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Mannose Receptor
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Mannose-Binding Lectins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Protein Subunits
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Receptors, Cell Surface
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Toll-Like Receptor 4
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Ovalbumin
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Primaquine