Altered peptide ligand-mediated TCR antagonism can be modulated by a change in a single amino acid residue within the CDR3 beta of an MHC class I-Restricted TCR

The Ag receptor of cytotoxic CD8(+) T lymphocytes recognizes peptides of 8- 10 aa bound to MHC class I molecules. This rig recognition event leads to t he activation of the CD8(+) lymphocyte and subsequent lysis of the target c ell. Altered peptide ligands are analogues derived from the original antige nic peptide that commonly carry amino acid substitutions at TCP contact res idues. TCR engagement by these altered peptide ligands usually impairs norm al T cell function. Some of these altered peptide ligands (antagonists) are able to specifically antagonize and inhibit T cell activation induced by t he wild-type antigenic peptide. Despite significant advances made in unders tanding TCR antagonism, the molecular interactions between the TCR and the MHC/peptide complex responsible for the inhibitory activity of antagonist p eptides remain elusive. To approach this question, we have identified alter ed peptide ligands derived from the vesicular stomatitis virus peptide (RGY VYQGL) that specifically antagonize an H-2K(b)/ vesicular stomatitis virus- specific TCR. Furthermore, by site-directed mutagenesis, we altered single amino acid residues of the complementarity-determining region 3 of the beta -chain of this TCR and tested the effect of these point mutations on Ag rec ognition and TCR antagonism. Here we show that a single amino acid change o n the TCR CDR3 beta loop can modulate the TCR-antagonistic properties of an altered peptide Ligand, Our results highlight the role of the TCR compleme ntarity-determining region 3 loops for controlling the nature of the T cell response to TCR/altered peptide ligand interactions, including those leadi ng to TCR antagonism.