X-ray crystallographic analyses of antigen:antibody complexes have shown that the hypervariable loops (complementarity-determining regions, CDRs) of immunoglobulin V regions determine the binding specificity of an antibody. Contact between an antibody molecule and a protein antigen usually occurs over a broad area of the antibody surface that is complementary to the surface recognized on the antigen. Electrostatic interactions, hydrogen bonds, van der Waals forces, and hydrophobic and pi-cation interactions can all contribute to binding. Depending on the size of the antigen, amino acid side chains in most or all of the CDRs make contact with antigen and determine both the specificity and the affinity of the interaction. Other parts of the V region normally play little part in the direct contact with the antigen, but they provide a stable structural framework for the CDRs and help to determine their position and conformation. Antibodies raised against intact proteins usually bind to the surface of the protein and make contact with residues that are discontinuous in the primary structure of the molecule; they may, however, occasionally bind peptide fragments of the protein, and antibodies raised against peptides derived from a protein can sometimes be used to detect the native protein molecule. Peptides binding to antibodies usually bind in a cleft or pocket between the V regions of the heavy and light chains, where they make specific contact with some, but not necessarily all, of the CDRs. This is also the usual mode of binding for carbohydrate antigens and small molecules such as haptens.
Antigen recognition by T cells.
In contrast to the immunoglobulins, which interact with pathogens and their toxic products in the extracellular spaces of the body, T cells recognize foreign antigens only when they are displayed on the surface of the body’s own cells. These antigens can derive from pathogens such as viruses or intracellular bacteria, which replicate within cells, or from pathogens or their products that have been internalized by endocytosis from the extracellular fluid.
T cells detect the presence of an intracellular pathogen because the infected cells display peptide fragments of the pathogen’s proteins on their surface. These foreign peptides are delivered to the cell surface by specialized host-cell glycoproteins—the MHC molecules. These are encoded in a large cluster of genes that were first identified by their powerful effects on the immune response to transplanted tissues. For that reason, the gene complex was called the major histocompatibility complex (MHC), and the peptide-binding glycoproteins are known as MHC molecules. The recognition of antigen as a small peptide fragment bound to an MHC molecule and displayed at the cell surface is one of the most distinctive features of T cells, and will be the focus of this part of the chapter. How the peptide fragments of antigen are generated and become associated with MHC molecules will be described in Chapter 6.
We describe here the structure and properties of the T-cell receptor (TCR). As might be expected from the T-cell receptors’ function as highly variable antigen-recognition structures, the genes for TCRs are closely related to those for immunoglobulins. There are, however, important differences between T-cell receptors and immunoglobulins, and these differences reflect the special features of antigen recognition by T cells.
4-11 The TCRα:β heterodimer is very similar to a Fab fragment of immunoglobulin.