Fig. 6.9 The MHC class I peptide-loading complex includes the chaperones calreticulin, ERp57, and tapasin. This model shows a side (a) and top view (b) of the peptide-loading complex (PLC) oriented as it extends from the luminal surface of the endoplasmic reticulum. The newly synthesized MHC class I and β2-microglobulin are shown as yellow ribbons, with the α helices of the MHC peptide-binding groove clearly identifiable. The MHC and tapasin (cyan) would be tethered to the membrane of the endoplasmic reticulum by carboxy-terminal extensions not shown here. Tapasin and ERp57 (green) form a heterodimer linked by a disulfide bond, and tapasin makes contacts with the MHC molecule that stabilize the empty conformation of the peptide-binding groove; they function in editing peptides binding to the MHC class I molecule. Calreticulin (orange), like the calnexin it replaces (see Fig. 6.8), binds to the monoglucosylated N-linked glycan at asparagine 86 of the immature MHC molecule. The long, flexible P domain of calreticulin extends around the top of the peptide-binding groove of the MHC molecule to make contact with ERp57. The transmembrane region of tapasin (not shown) associates the PLC with TAP (see Fig. 6.8), bringing the empty MHC molecules into proximity with peptides arriving into the endoplasmic reticulum from the cytosol. Structure based on PDB file provided by Karin Reinisch and Peter Cresswell.
class I assembly or antigen processing. However, we will see in Chapter 13 how many viral pathogens co-opt the ERAD pathways to block assembly of MHC class I molecules as a way to evade recognition by CD8 T cells.
In uninfected cells, peptides derived from self proteins fill the peptide-binding groove of the mature MHC class I molecules and are carried to the cell surface. In normal cells, MHC class I molecules are retained in the endoplasmic reticulum for some time, which suggests that they are present in excess of peptide. This is important for the immunological function of MHC class I molecules, which must be immediately available to transport viral peptides to the cell surface if the cell becomes infected.
6-5 Dendritic cells use cross-presentation to present exogenous proteins on MHC class I molecules to prime CD8 T cells.
The pathway described above explains how proteins synthesized in the cytosol can generate peptides that become displayed as complexes with MHC class I molecules on the cell surface. This pathway is sufficient to ensure detection and destruction of pathogen-infected cells by cytotoxic T cells. But how do these cytotoxic T cells first become activated? Our explanation so far would require that dendritic cells become infected as well, so that they express the peptide:MHC class I complex needed to activate naive CD8 T cells. But many viruses exhibit a restricted tropism for different cells types, and not all viruses will infect dendritic cells. This creates the chance that antigens from such pathogens might never be displayed by dendritic cells, and that cytotoxic T cells that recognize them might not be activated. As it turns out, certain dendritic cells are able to generate peptide:MHC class I complexes from peptides that were not generated within their own cytosol. Peptides from extracellular sources—such as viruses, bacteria, and phagocytosed dying cells infected with cytosolic pathogens—can be presented on MHC class I molecules on the surface of these dendritic cells by the process of cross-presentation.