Processing of Proteins to Allow Peptide Presentation by MHC Molecules

PROCESSING OF PROTEINS TO ALLOW PEPTIDE PRESENTATION BY MHC MOLECULES

Peptide epitope presented by MHC I is derived from the processing of proteins (e.g. a viral protein) synthesized within the actual cell that eventually will present the peptide to cytotoxic T-lymphocytes. The MHC I molecule is composed of two polypeptide chains, an α chain which has α1, α2 and α3 domains, and a second polypeptide termed β2-microglobulin. The α1 and β2 domains form a peptide-binding cleft which can accommodate peptides up to 11 amino acids in length. Figure 9.9a shows the processing of a protein into peptide fragments for presentation by MHC I. The synthesized protein (indicated by an asterisk) is present in the cytoplasm of the cell and is degraded by a subcellular organelle termed a proteasome. The derived peptide fragments are actively transported, via a TAP peptide transporter, into the lumen of the endoplasmic reticulum (ER) where they fit within the binding clefts of MHC I molecules. From the ER the MHC I with bound peptide is transported to the trans-Golgi network (TGN), from which it is transported via endosomes to the plasma membrane where the MHC I molecule with bound peptide is accessible to surveillance by cytotoxic CD8+ T-lymphocytes.

Peptide epitopes presented by MHC II are derived from proteins present within the extracellular fluid and are presented to helper T-lymphocytes by APCs. The MHC II molecule is composed of two polypeptide chains, an α-chain which has α1 and α2 domains, and a β-chain which has β1 and β2 domains. The α1 and β1 domains form a peptide-binding cleft that can accommodate peptides up to 20 amino acids in length. Figure 9.9b shows the processing of a protein into peptide fragments for presentation by MHC II. In this case the protein (indicated by an asterisk) is internalized from the extracellular fluid by the APC and restricted to an endosomal compartment without access to the APC’s cytoplasm. The endosome delivers the protein to a lysosome compartment which degrades the protein into peptide fragments, after which the peptide fragments are returned to an endosome compartment. In the lumen of the ER the MHC II molecule becomes associated with another protein termed an invariant chain which blocks access of peptides to the binding cleft of the MHC II molecule; the MHC II–invariant chain complex is transferred to the TGN and then to an endosomal compartment. At this point the endosomes that contain the processed peptide and the MHC II molecules merge, and the invariant chain disintegrates, allowing peptides access to the MHC II-binding cleft. The MHC II molecules with bound peptide are transported to the plasma membrane where they are accessible to surveillance by helper CD4+ T-lymphocytes.