IV. Unconventional Hypervariable Regions

In addition to the three classical hypervariable regions which constitute the complementarity-determining regions (CDRs) in immunoglobulins, the TCR contains a fourth region of hypervariability in each of its polypeptide chains. These regions occur away from the antigen-binding face of the receptor, and have been implicated in other functions of the TCR, such as superantigen binding.

Superantigens were first discovered for their ability to stimulate large numbers of T cell clones bearing several distinct antigen receptors. Mutational analysis of the TCR has shown that these superantigens bind certain amino acid residues on the lateral face of the molecule, away from the classical antigen combining site. These residues lie in the fourth hypervariable region of the beta chain, designated HV4 (69-78β). HV4 itself is unremarkable, occupying a loop and outer beta strand on the exposed surface of Vβ. The evolution of this fourth region of hypervariabilty may indicate a specific purpose in binding MHC ligands or other activation molecules that has been preserved despite the high cost of clonal deletion in the presence of superantigens. Conversely, HV4 may have evolved to combat clonal deletion by expanding the T cell repertoire, thus escaping superantigen exploitation of the exposed Vβ surface.

Other residues in Vβ have been found outside of HV4 which also participate in superantigen binding. Residues such as Asn24β in the 2C TCR occupy sites adjacent to HV4 in the tertiary structure of the molecule, and can affect superantigen binding by mere proximity. Also important, however, are residues within the antigen combining site of the receptor. Residues such as Gly51β and Gly53β, which lie at the apex of CDR2, have been implicated in bacterial superantigen binding, and reveal the large surface area of Vβ utilized by superantigens.

The fourth hypervariable region in the alpha chain (65-72α) is designated α4, and likewise occurs on the lateral surface of the TCR, away from the antigen combining site. α4 resides on portions of two adjacent beta strands, as well as the separating beta turn, and is completely exposed to solvent. No known superantigens bind α4, perhaps because of the orientation of the alpha and beta chains when bound to MHC ligands. Like HV4, the function of α4 (if any) is unknown.