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
- Research Support, Non-U.S. Gov't
MeSH terms
- ATP-Binding Cassette Transporters / chemistry
- ATP-Binding Cassette Transporters / immunology
- ATP-Binding Cassette Transporters / metabolism
- Animals
- Antigen Presentation
- Antigens / immunology
- Antigens / metabolism
- Cross-Priming
- Dendritic Cells / immunology*
- Dendritic Cells / metabolism
- Endosomes / metabolism
- Histocompatibility Antigens Class I / immunology*
- Histocompatibility Antigens Class I / metabolism
- Lectins, C-Type / deficiency
- Lectins, C-Type / genetics
- Mannose Receptor
- Mannose-Binding Lectins / deficiency
- Mannose-Binding Lectins / genetics
- Mice
- Mice, Knockout
- Myeloid Differentiation Factor 88 / immunology
- Ovalbumin / immunology
- Ovalbumin / metabolism
- Primaquine / pharmacology
- Protein Subunits / immunology
- Protein Transport / drug effects
- Receptors, Cell Surface / deficiency
- Receptors, Cell Surface / genetics
- Solubility
- T-Lymphocytes, Cytotoxic / immunology
- Toll-Like Receptor 4 / immunology
Substances
- ATP-Binding Cassette Transporters
- Antigens
- Histocompatibility Antigens Class I
- Lectins, C-Type
- Mannose Receptor
- Mannose-Binding Lectins
- Myd88 protein, mouse
- Myeloid Differentiation Factor 88
- Protein Subunits
- Receptors, Cell Surface
- Toll-Like Receptor 4
- Ovalbumin
- Primaquine