Fig. 4.28 CD4 and the T-cell receptor bind to distinct regions of the MHC class II molecule. A ribbon diagram is shown from a crystal structure of a complete α:β TcR:peptide-Mhc:cD4 ternary complex. The α and β chains of the T-cell receptor (TcR) are blue and red, respectively. The Mhc class ii molecule is green, with the bound peptide shown in gray. cD4 is shown in orange. Structure derived from PDB 3T0e. courtesy of K.c. garcia.
Fig. 4.29 CD8 binds to a site on MHC class I molecules that is distant from where the T-cell receptor binds. The relative binding positions of both the T-cell receptor and cD8 molecules can be seen in this hypothetical reconstruction of their interaction with Mhc class i (α chain in dark green and β2-microglobulin in light green). The α and β chains of the T-cell receptor are shown in brown and purple, respectively. The cD8αβ heterodimer is shown bound to the Mhc class i α3 domain. The cD8 α chain is in blue, and the cD8β chain is in red. courtesy of chris nelson and David fremont.
Mhc class i molecules are expressed on all nucleated cells, although they are most highly expressed in hematopoietic cells. Mhc class ii molecules are normally expressed only by a subset of hematopoietic cells and by thymic stromal cells, although they may be expressed by other cell types on exposure to the inflammatory cytokine ifn-γ. *in humans, activated T cells express Mhc class ii molecules, whereas in mice all T cells are Mhc class ii-negative. †in the brain, most cell types are Mhc class ii-negative, but microglia, which are related to macrophages, are Mhc class ii-positive.
4-19 The two classes of MHC molecules are expressed differentially on cells.
MHC class I and MHC class II molecules have distinct distributions among cells, and these reflect the different effector functions of the T cells that recognize them (Fig. 4.30). MHC class I molecules present peptides from pathogens, commonly viruses, to CD8 cytotoxic T cells, which are specialized to kill any cell that they specifically recognize. Because viruses can infect any nucleated cell, almost all such cells express MHC class I molecules, although the level of constitutive expression varies from one cell type to the next. For example, cells of the immune system express abundant MHC class I on their surface, whereas liver cells (hepatocytes) express relatively low levels (see Fig. 4.30). Nonnucleated cells, such as mammalian red blood cells, express little or no MHC class I, and thus the interior of red blood cells is a site in which an infection can go undetected by cytotoxic T cells. Because red blood cells cannot support viral replication, this is of no great consequence for viral infection, but it might be the absence of MHC class I that allows the Plasmodium parasites that cause malaria to live in this privileged site.
In contrast, a major function of the CD4 T cells that recognize MHC class II molecules is to activate other effector cells of the immune system. Thus, MHC class II molecules are normally found on dendritic cells, B lymphocytes, and macrophages—antigen-presenting cells that participate in immune responses—but not on other tissue cells (see Fig. 4.30). The peptides presented by MHC class II molecules expressed by dendritic cells can function to activate naive CD4 T cells. When previously activated CD4 T cells recognize peptides bound to MHC class II molecules on B cells, the T cells secrete cytokines that can influence the isotype of antibody that those B cells will choose to produce. Upon recognizing peptides bound to MHC class II molecules on macrophages, CD4 T cells activate these cells, again in part through cytokines, to destroy the pathogens in their vesicles.