Spatial and mechanistic separation of cross-presentation and endogenous antigen presentation.
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.
Burgdorf
Sven
S
Institute of Molecular Medicine and Experimental Immunology, Friedrich-Wilhelms University, 53105 Bonn, Germany. sven.burgdorf@ukb.uni-bonn.de
Schölz
Christian
C
Kautz
Andreas
A
Tampé
Robert
R
Kurts
Christian
C
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology / Q000378:metabolism; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D011319:Primaquine / Q000494:pharmacology; D021122:Protein Subunits / Q000276:immunology; D021381:Protein Transport / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics; D012995:Solubility; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
D018528:ATP-Binding Cassette Transporters; D000941:Antigens; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D021122:Protein Subunits; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D010047:Ovalbumin; D011319:Primaquine