cells recognize short antigenic peptides bound to major histocompatibility complex (MHC) molecules. Engagement of the T-cell receptor (TCR) determines not only the fate of the cell during thymic selection, but also its survival in the periphery and, eventually, the extent of functional activation 1 . The TCR enables the cellular arm of the acquired immune system to recognize distinct antigens derived from foreign or selfproteins. However, it remains unresolved how the diverse protective repertoire of host T cells is selected in the thymus without frequently leading to autoimmunity 2 .
How specific is the TCR?
Two separate crystal structures of a TCR complexed with its peptide-MHC ligand have recently been published . When contacting the peptide-MHC complex, the TCR rather unexpectedly exposes a flat surface with only one pocket where the Vโฃ and Vโค regions join each other . In addition, most of the interaction surface comprises the TCR contacting the MHC molecule, rather than the peptide.
Even more surprisingly, stable TCR-MHC complexes are formed when the peptide is modified in a key TCR contact position from a Tyr residue to Ala (Ref. 5). This indicates that TCR-MHC interactions contribute substantially to the binding within the trimolecular complex 6,7 , suggesting a lessstringent T-cell recognition of actual antigenic peptide.
These considerations are supported by recent studies involving extensive mapping of various T-cell epitopes. Using sets of peptides substituted at single amino acids, it became clear that many modifications of the antigenic peptide are tolerated . Interestingly, at least in autoreactive T cells, some of the modifications resulted in peptides that are even more potent than the native antigen; these peptides have been termed superagonists . Moreover, such amino acid modifications could compensate for other alterations of the ligand, even if these involved nonconservative exchanges of the primary TCR contact 11 . This observation, and the wide range of tolerated amino acids, argue for a large number of stimulatory ligands for a single TCR.