The many roads to cross-presentation

Abstract

Cross-presentation of extracellular antigens by MHC class I molecules is required for priming cytotoxic T lymphocytes (CTLs) at locations remote from the site of infection. Various mechanisms have been proposed to explain cross-presentation. One such mechanism involves the fusion of the endoplasmic reticulum (ER) with the endosomal-phagosomal system, in which the machinery required for peptide loading of MHC class I molecules is introduced directly into the phagosome. Here, we discuss the evidence for and against the ER-phagosome concept as well as other possible mechanisms of cross-presentation.

Figure 1.

Various models of cross-presentation. In the classical MHC class I antigen–presenting pathway, intracellular antigens are degraded by the proteasome and peptidases. A fraction of the resulting peptides associate with TAP in the ER membrane where newly synthesized MHC class I molecules are arrested until loaded with peptide. MHC class I–peptide complexes then leave the ER and are transported to the plasma membrane. Extracellular antigens can enter this pathway in various ways. (A) Gap junctions allow direct transfer of peptides from infected cells into the cytosol of DCs. (B) MHC class I molecules can enter the recycling pathway and exchange peptides. (C) ER components become an integral part of the phagosomal pathway. The ERAD pathway then exports exogenous antigen from the phagosome into the cytosol and phagosomal TAP allows retro-transport of peptides back into the phagosome. (D) Exogenous antigens can be transported over the endosomal membrane. (E) Exosomes secreted by infected cells can bind to DCs for cross-presentation.

Figure 2.

Beadosomes, ER, ribosomes, and mitochondria in a DC. 1-μm latex beads were endocytosed by human monocyte-derived DCs for 30 min before processing for electron microscopy. The cells were fixed with a mixture of formaldehyde and glutaraldehyde and embedded in epon for thin sectioning. The bead, mitochondria (Mt), and two ER profiles are indicated. The arrowheads point to ribosomes in association to the ER membrane. No such structures are observed on the beadosomal membrane. The box denotes a position in the section with lower resolution where the ER is apposite to the mitochondrion. Bar, 200 nm.