Extensive trafficking of MHC class II-invariant chain complexes in the endocytic pathway and appearance of peptide-loaded class II in multiple compartments.

Major histocompatibility complex class II molecules bind and present to T cells fragments of protein antigens entering the endocytic pathway. Using normal B lymphoblasts, we have combined metabolic pulse-chase labelling, high resolution organelle fractionation, and immunoprecipitation to examine class II trafficking and antigen loading in a physiological model system. Most newly synthesized class II-invariant chain complexes first entered early endosomes, then accessed multiple discrete endocytic subcompartments cofractionating with late endosomes and immature lysosomes. Invariant chain was removed and peptide-loaded class II molecules appeared in each of these latter distinct organelles. These findings suggest that class II molecules traffic through much of the endocytic pathway, permitting capture of distinct determinants made available under differing conditions of pH and proteolytic activity.