Fig. 6.15 Activation of dendritic cells reduces MARCH-1 expression, thus increasing the lifetime of MHC molecules. Before activation by innate recognition of pathogens, dendritic cells express the membrane-associated E3 ligase MARCH-1, which resides in the recycling endosomes compartment, where it attaches K-48-linked ubiquitin chains to the β chain of MHC class II molecules. This causes MHC molecules to move from the recycling endosomes and eventually to be degraded, leading to a reduced overall half-life and level of MHC expression on the cell surface. Signals emanating from innate sensors, such as TLR-4, reduce the level of MARCH-1 mRNA, and with the half-life of MARCH-1 now being short, MHC molecules are free to accumulate on the cell surface. Because innate signaling also triggers acidification of endocytic compartments and activates caspases associated with antigen processing, the MHC molecules that accumulate on the cell surface will bear peptides from the pathogens captured around the time of innate activation of the dendritic cells.
regulated by ubiquitination. This means that by the time dendritic cells arrive at lymph nodes, they express peptides derived from the pathogens that activated them and have higher CD86 levels that provide signals for greater CD4 T-cell activation. However, we will see in Chapter 13 that viral pathogens have taken advantage of this pathway by producing MARCH-1-like proteins to downregulate MHC class II molecules as a means of evading adaptive immunity.
Summary.
The ligand recognized by the T-cell receptor is a peptide bound to an MHC molecule. MHC class I and MHC class II molecules acquire peptides at different intracellular sites and activate either CD8 or CD4 T cells, respectively. Infected cells presenting peptides derived from virus replication in the cytosol are thus recognized by CD8 cytotoxic T cells, which are specialized to kill any cells displaying foreign antigens. MHC class I molecules are synthesized in the endoplasmic reticulum and typically acquire their peptides at this location. The peptides loaded onto MHC class I molecules are derived from proteins degraded in the cytosol by the proteasome, transported into the endoplasmic reticulum by the heterodimeric ATP-binding protein TAP, and further processed by the aminopeptidase ERAAP before being loaded onto the MHC molecules. Peptide binding to MHC class I molecules is required for them to be released from chaperones in the endoplasmic reticulum and to travel to the cell surface. Certain subsets of dendritic cells are able to produce peptides from exogenous proteins and load them onto MHC class I molecules. Such cross-presentation of antigens ensures that CD8 T cells can be activated by pathogens that may not directly infect antigen-presenting cells.
MHC class II molecules do not acquire their peptide ligands in the endoplasmic reticulum, because the invariant chain (Ii) first inserts CLIP into their peptide-binding groove. Association with Ii targets these MHC molecules to an acidic endosomal compartment where active proteases cleave Ii, and HLA-DM helps to catalyze dissociation of CLIP. The MHC molecules can then associate with peptides derived from proteins that have entered the vesicular compartments of macrophages, dendritic cells, or B cells. The process of autophagy can deliver cytosolic proteins to the vesicular system for presentation by MHC class II molecules. The CD4 T cells that recognize peptide:MHC class II complexes have a variety of specialized effector activities. Subsets of CD4 T cells activate macrophages to kill the intravesicular pathogens they harbor, help B cells to secrete immunoglobulins against foreign molecules, and regulate immune responses.
The major histocompatibility complex and its function.