For loading peptides onto MHC class II molecules, dendritic cells, macrophages, and B cells are able to capture exogenous proteins via endocytic vesicles and through specific cell-surface receptors. For B cells, this process of antigen capture can include the B-cell receptor. The peptides that are derived from these proteins are loaded onto MHC class II molecules in specially modified endocytic compartments in these antigen-presenting cells, which we will discuss in more detail later. In dendritic cells, this pathway operates to activate naive CD4 T cells to become effector T cells. Macrophages take up particulate material by phagocytosis and so mainly present pathogen-derived peptides on MHC class II molecules. In macrophages, such antigen presentation may be used to indicate the presence of a pathogen within its vesicular compartment. Effector CD4 T cells, on recognizing antigen, produce cytokines that can activate the macrophage to destroy the pathogen. Some intravesicular pathogens have adapted to resist intracellular killing, and the macrophages in which they live require these cytokines to kill the pathogen: this is one of the roles of the TH1 subset of CD4 T cells. Other CD4 T cell subsets have roles in regulating other aspects of the immune response, and some CD4 T cells even have cytotoxic activity. In B cells, antigen presentation may serve to recruit help from CD4 T cells that recognize the same protein antigen as the B cell. By efficiently endocytosing a specific antigen via their surface immunoglobulin and presenting the antigen-derived peptides on MHC class II molecules, B cells can activate CD4 T cells that will in turn serve as helper T cells for the production of antibodies against that antigen.
Beyond the presentation of exogenous proteins, MHC class II molecules can also be loaded with peptides derived from cytosolic proteins by a ubiquitous pathway of autophagy, in which cytoplasmic proteins are delivered into the endocytic system for degradation in lysosomes (Fig. 6.4). This pathway can serve in the presentation of self-cytosolic proteins for the induction of tolerance to self antigens, and also as a means for presenting antigens from pathogens, such as herpes simplex virus, that have accessed the cell’s cytosol.
6-2 Peptides are generated from ubiquitinated proteins in the cytosol by the proteasome.
Proteins in cells are continually being degraded and replaced with newly synthesized proteins. Much cytosolic protein degradation is carried out by a large, multicatalytic protease complex called the proteasome (Fig. 6.5). A typical proteasome is composed of one 20S catalytic core and two 19S regulatory caps, one at each end; both the core and the caps are multisubunit complexes of proteins. The 20S core is a large cylindrical complex of some 28 subunits, arranged in four stacked rings of seven subunits each around a hollow core. The two outer rings are composed of seven distinct α subunits and are noncatalytic. The two inner rings of the 20S proteasome core are composed of seven distinct β subunits. The constitutively expressed proteolytic subunits are β1, β2, and β5, which form the catalytic chamber. The 19S regulator is composed of a base containing nine subunits that binds directly to the α ring of the 20S core particle and a lid that has up to 10 different subunits. The association of the 20S core with a 19S cap requires ATP as well as the ATPase activity of many of the caps’ subunits. One of the 19S caps binds and delivers proteins into the proteasome, while the other keeps them from exiting prematurely.