Peptides Are Generated from Internalized Molecules in Endocytic Vesicles

Once an antigen is internalized, it is degraded into peptides within compartments of the endocytic processing pathway. As the experiment shown in Figure 8-3 demonstrated, internalized antigen takes 1-3 h to transverse the endocytic pathway and appear at the cell surface in the form of peptide-class II MHC complexes. The endocytic pathway appears to involve three increasingly acidic compartments: early endosomes (pH 6.0-6.5); late endosomes, or endolysosomes (pH 5.0-6.0); and lysosomes (pH 4.5-5.0). Internalized antigen moves from early to late endosomes and finally to lysosomes, encountering hydrolytic enzymes and a lower pH in each compartment (Figure 8-9). Lysosomes, for example, contain a unique collection of more than 40 acid-dependent hydrolases, including proteases, nucleases, glycosidases, lipases, phospholipases, and phosphatases. Within the compartments of the endocytic pathway, antigen is degraded into oligopeptides of about 1318 residues, which bind to class II MHC molecules. Because the hydrolytic enzymes are optimally active under acidic conditions (low pH), antigen processing can be inhibited by chemical agents that increase the pH of the compartments (e.g., chloroquine) as well as by protease inhibitors (e.g., leupeptin).

The mechanism by which internalized antigen moves from one endocytic compartment to the next has not been conclusively demonstrated. It has been suggested that early endosomes from the periphery move inward to become late endosomes and finally lysosomes. Alternatively, small transport vesicles may carry antigens from one compartment to the next. Eventually the endocytic compartments, or portions of them, return to the cell periphery, where they fuse with the plasma membrane. In this way, the surface receptors are recycled.

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