A MOLECULAR-BASIS FOR HOW A SINGLE TCR INTERFACES MULTIPLE LIGANDS

CD8(+) T cells respond to Ags when their clonotypic receptor, the TCR, recognizes nonself peptides displayed by MHC class I molecules. The T CR/ligand interactions are degenerate because, in its life time, the T CR interacts with self MHC class I-self peptide complexes during ontog eny and with self class I complexed with nonself peptides to initiate Ag-specific responses. Additionally, the same TCR has the potential to interact with nonself class I complexed with nonself peptides, How a single TCR interfaces multiple ligands remains unclear. Combinatorial synthetic peptide libraries provide a powerful tool to elucidate the r ules that dictate how a single TCR engages multiple ligands, Such libr aries were used to probe the requirements for TCR recognition by clone d CD8(+) T cells directed against Ags presented by H-2K(b) class I mol ecules. When H-2K(b) contact residues were examined, position 3 of the peptides proved more critical than the dominant carboxyl-terminal anc hor residue, Thus, secondary anchor residues can play a dominant role in determining the antigenicity of the epitope presented by class I mo lecules. When the four solvent-exposed potential TCR contact residues were examined, only one or two of these positions required structurall y similar residues. Considerable structural variability was tolerated at the remaining two or three solvent-exposed residues of the K-b-bind ing peptides, The TCR, therefore, requires close physico-chemical comp lementarity with only a few amino acid residues, thus explaining why T CR/MHC interactions are of low affinity and degenerate.