MHC proteins capture and display peptide fragments of foreign proteins for presentation to T cells. There are two main classes of MHC proteins, which are structurally and functionally distinct. Class I MHC proteins mainly present foreign peptides to cytotoxic T cells, whereas class II MHC proteins mainly present foreign peptides to helper and regulatory T cells (Figure 24–35). Some class-I-like MHC proteins present microbial lipid and glycolipid antigens to T cells, but they are not encoded within the MHC region of the genome, and we will not consider them further.
Figure 24–33 Immunofluorescence micrograph of a dendritic cell in culture.
These Apcs derive their name from their long processes, or “dendrites.” The cell has been labeled with a monoclonal antibody that recognizes a surface antigen on these cells. (courtesy of David Katz.)
Both class I and class II MHC proteins are heterodimers, in which two extracellular domains form a peptide‑binding groove, which always has a variable small peptide bound in it. In class I MHC proteins, the two domains that form the pep-tide-binding groove are provided by the transmembrane αchain, which is noncovalently associated with a small subunit called β2-microglobulin; in class II MHC proteins, a different α chain and a large noncovalently associated β chain each contribute an extracellular domain to form the peptide-binding groove (Figure 24–36). A TCR binds to both the peptide and the ridges of the binding groove. Humans have three major class I proteins, called HLA‑A, HLA‑B, and HLA‑C, and three class II proteins, called HLA‑DR, HLA‑DP, and HLA‑DQ (HLA stands for human-leukocyte-associated, as these proteins were first demonstrated on human leukocytes). Figure 24–37 shows how the genes that encode these proteins are arranged on human chromosome 6.
There are important differences between the class I and class II MHC proteins with regard to the cell types that express them and the origin of the peptides in their peptide-binding grooves. Almost all of our nucleated cells express class I proteins. Their peptide-binding groove displays one of a diverse collection of peptides (typically 8–10 amino acids in length). In a healthy cell, the peptides originate from the cell’s own cytosolic and nuclear proteins that have undergone partial degradation in proteasomes in the processes of normal protein turnover and quality control mechanisms. Some of the peptide fragments produced in this way are actively transported into the lumen of the endoplasmic reticulum (ER), through a specialized transporter in the ER membrane, where they are loaded onto newly synthesized class I MHC α chains; once a peptide binds, the α chain can assemble with its partner chain. The resulting self-peptide–MHC complex is then transported through the Golgi apparatus to the cell surface. Such complexes are not dangerous, however, because the cytotoxic T cells that could recognize fragment MHC of foreign MHC of foreign protein
Figure 24–34 The three general types of proteins on the surface of an activated dendritic cell involved in activating a T cell. Although only membrane-bound co-stimulatory molecules are shown, activated dendritic cells also secrete soluble co-stimulatory molecules. The invariant polypeptide chains that are  always stably associated with the Tcr are not shown; they are illustrated  in Figure 24–45B and Movie 24.7.