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.
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We thank M.C. Nussenzweig (Rockefeller University) for mannose receptor-deficient mice; W.R. Heath (The Walter and Eliza Hall Institute of Medical Research) for OT-I and OT-II mice; R. Germain (National Institutes of Health) for 25-D1.16; A. Haas for the transferrin receptor antibody; and P. Knolle for critically reading the manuscript. We acknowledge the technical support of the flow cytometry core facility of the Institute of Molecular Medicine and Experimental Immunology and the House for Experimental Therapy of the Medical Faculty of Bonn University. Supported by the BONFOR program of Friedrich-Wilhelms University (O-173.0009 to S.B.) and by the Deutsche Forschungsgemeinschaft (SFB704 to C.K. and Ta157/7-1 to R.T.).
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Burgdorf, S., Schölz, C., Kautz, A. et al. Spatial and mechanistic separation of cross-presentation and endogenous antigen presentation. Nat Immunol 9, 558–566 (2008). https://doi.org/10.1038/ni.1601
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