Spatial and Mechanistic Separation of Cross-Presentation and Endogenous Antigen Presentation

Nat Immunol. 2008 May;9(5):558-66. doi: 10.1038/ni.1601. Epub 2008 Mar 30.

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-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-Binding Lectins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Protein Subunits
  • Receptors, Cell Surface
  • Toll-Like Receptor 4
  • mannose receptor
  • Ovalbumin
  • Primaquine