The immunological function of MHC class II molecules is to bind peptides generated in the intracellular vesicles of dendritic cells, macrophages, and B cells, and to present these peptides to CD4 T cells. The purpose for this pathway is different for each cell type. Dendritic cells primarily are concerned with activating CD4 T cells, while macrophages and B cells are concerned with receiving various forms of help from these CD4 T cells. For example, the intracellular vesicles of macrophages are the sites of replication for several types of pathogens, including the protozoan parasite Leishmania and the mycobacteria that cause leprosy and tuberculosis. Because these pathogens reside in membrane-enclosed vesicles, the proteins of these pathogens are not usually accessible to proteasomes in the cytosol. Instead, after activation of the macrophage, the pathogens are degraded by activated intravesicular proteases into peptide fragments that can bind to MHC class II molecules, which pass through this compartment on their way from the endoplasmic reticulum to the cell surface. Like all membrane proteins, MHC class II molecules are first delivered into the endoplasmic reticulum membrane, and are then transported onward as part of membrane-enclosed vesicles that bud off the endoplasmic reticulum and are directed to intracellular vesicles containing internalized antigens. Complexes of peptides and MHC class II molecules are formed there and are then delivered to the cell surface, where they can be recognized by CD4 T cells.
Antigen processing for MHC class II molecules begins when extracellular pathogens and proteins are internalized into endocytic vesicles (Fig. 6.10). Proteins that bind to surface immunoglobulin on B cells and are internalized by receptor-mediated endocytosis are processed by this pathway. Larger particulate materials, such as fragments of dead cells, are internalized by phagocytosis, particularly by macrophages and dendritic cells. Soluble proteins, such as secreted toxins, are taken up by macropinocytosis. Proteins that enter cells through endocytosis are delivered to endosomes, which become
Vesicles containing peptides fuse with vesicles containing MHC class II molecules Acidifcation of vesicles activates proteases to degrade antigen into peptide fragments Antigen is taken up from the extracellular space into intracellular vesicles extracellular space cytosol In early endosomes of neutral pH, endosomal proteases are inactive
Fig. 6.10 Peptides that bind to MHC class II molecules are generated in acidified endocytic vesicles.
In the case illustrated here, extracellular foreign antigens, such as bacteria or bacterial antigens, have been taken up by an antigen-presenting cell such as a macrophage or an immature dendritic cell. In other cases, the source of the peptide antigen may be bacteria or parasites that have invaded the cell to replicate in intracellular vesicles. In both cases the antigen-processing pathway is the same. The pH of the endosomes containing the engulfed pathogens decreases progressively, activating proteases within the vesicles to degrade the engulfed material. At some point on their pathway to the cell surface, newly synthesized MHC class II molecules pass through such acidified vesicles and bind peptide fragments of the antigen, transporting the peptides to the cell surface.
increasingly acidic as they progress into the interior of the cell, eventually fusing with lysosomes. The endosomes and lysosomes contain proteases, known as acid proteases, that are activated at low pH and eventually degrade the protein antigens contained in the vesicles.