Fig. 5.5 TheT-cellreceptor(TCR)complexandothermoleculesinvolvedinT-cellactivation.TheTCRheterodimer,consistingofanα chainandaβ chain,recognizesantigen(intheformofpeptide-MHCcomplexesexpressedonantigen-presentingcells),andthelinkedCD3complexandζ chainsinitiateactivatingsignals.CD4andCD28arealsoinvolvedinT-cellactivation.(NotethatsomeTcellsexpressCD8andnotCD4;thesemoleculesserveanalogousroles.)Thesizesofthemoleculesarenotdrawntoscale.MHC, Majorhistocompatibilitycomplex.
Major Histocompatibility Complex Molecules: The Peptide Display System of Adaptive Immunity
MHC molecules are fundamental to T-cell recognition of antigens, and genetic variations in MHC molecules are associated with many immunologic diseases; hence, it is important to review the structure and function of these molecules. The MHC was discovered on the basis of studies of graft rejection and acceptance (tissue, or “histo,” compatibility). It is now known that the normal function of MHC molecules is to display peptides for recognition by CD4+ and CD8+ T lymphocytes. In each person, T cells recognize only peptides displayed by that person’s MHC molecules, which, of course, are the only MHC molecules that the T cells normally encounter. This phenomenon is called MHC restriction.
The human MHC, known as the human leukocyte antigen (HLA) complex, consists of a cluster of genes on chromosome 6 (
Fig. 5.6 ). On the basis of their chemical structure, tissue distribution, and function, MHC gene products fall into two main categories: • Class I MHC molecules are expressed on all nucleated cells and are encoded by three closely linked loci, designated HLA-A, HLA-B, and HLA-C (see
Fig. 5.6 ). Each of these molecules consists of a polymorphic α chain noncovalently associated with an invariant β2microglobulin polypeptide (encoded by a separate gene on chromosome 15). The extracellular portion of the α chain contains a cleft where the polymorphic residues are located and where foreign peptides bind to MHC molecules for presentation to T cells, and a conserved region that binds CD8, ensuring that only CD8+ T cells can respond to peptides displayed by class I molecules. In general, class I MHC molecules bind and display peptides derived from protein antigens present in the cytosol of the cell (e.g., viral and tumor antigens).
Class II MHC molecules are encoded by genes in the HLA-D region, which contains three subregions: DP, DQ, and DR. Class II molecules are heterodimers of noncovalently linked α and β subunits (see
Fig. 5.6 ). Unlike class I MHC molecules, which are expressed on all nucleated cells, expression of class II MHC molecules is restricted to a few cell types, mainly APCs (notably, dendritic cells), macrophages, and B cells. The extracellular portion of class II MHC molecules contains a cleft for the binding of antigenic peptides and a region that binds CD4. In general, class II MHC molecules bind to peptides derived from extracellular proteins synthesized outside the cell, for example, from microbes that are ingested and then broken down inside the cell. This property allows CD4+ T cells to recognize the presence of extracellular pathogens.
Several other proteins are encoded in the MHC locus, including complement components (C2, C3, and Factor
B) and the cytokines tumor necrosis factor (TNF) and lymphotoxin.