1118

The diversity created by somatic recombination of TCR genes is estimated to exceed 10¹⁰ unique receptors. Combinatorial use of different V, D, and J gene segments makes an important contribution to this diversity, as do the mechanisms of junctional imprecision and N-nucleotide addition already discussed for immunoglobulin gene rearrangements. The net result is a degree of variability in the V regions that matches that of the immunoglobulins (see Figure 23-13). Indeed, each of the TCR’s variable regions includes three hypervariable regions (CDRs), equivalent to those in the BCR. Unlike immunoglobulin genes, however, the TCR genes do not undergo somatic hypermutation. Therefore, TCRs exhibit nothing equivalent to the affinity maturation of antibodies during the course of an immune response, nor is there the option of class-switch recombination or the use of alternative polyadenylation sites to create soluble and membrane-bound versions of the receptors.

The crystal structures of a number of TCRs bound to class I MHC–peptide or class II MHC–peptide complexes have been determined. These structures show variation in how the TCR docks with the MHC-peptide complex, but the most extensive contacts in the somatically diverse CDR3 region are made with the central peptide-containing portion of the complex, with the germ line–encoded CDR1 and CDR2 contacting the α helices of the MHC molecules. Many of the TCRs for which a structure has been solved dock diagonally across the peptide-binding portion of the MHC-peptide complex. As a result, the TCR makes extensive contacts with the peptide as well as with the α helices of the MHC molecule to which it binds. The positions at which allelic MHC molecules differ from one another are frequently those residues that directly contact the TCR, thus precluding tight binding of unrelated allelic MHC products.

Amino acid differences that distinguish one MHC allele from another also affect the architecture of the peptide-binding cleft. Even if the MHC residues that interact directly with the TCR were shared by two allelic MHC molecules, their peptide-binding specificity would probably differ because of amino acid differences in the peptide-binding cleft. Consequently, the TCR contact residues provided by bound peptide, which are essential for stable interaction with a TCR, would be absent from the “wrong” MHC-peptide combination. A productive interaction with the TCR would then be unlikely to occur.