DIFFERENTIAL CONTACT OF DISPARATE CLASS-I PEPTIDE COMPLEXES AS THE BASIS FOR EPITOPE CROSS-RECOGNITION BY A SINGLE T-CELL RECEPTOR

In an effort to better understand functional recognition of structural ly dissimilar ligands by a single TCR, a model system for studying cro ss-recognition of disparate peptide/class I complexes was developed us ing the murine (H-2(b)) CTL clone AHIII12.2, which is reactive to a hu man self-peptide (p1049) bound to an HLA-A2.1 molecule. We identified a second complex comprised of a synthetic peptide, designated p1058, b ound to H-2D(b) that is recognized by clone AHIII12.2. In cytolysis as says, dose-response profiles for peptides p1049 and p1058 pulsed onto the appropriate target cells were comparable, suggesting that p1049/A2 .1 and p1058/D-b form functionally equivalent epitopes. To probe the i nteraction between each complex and the TCR of AHIII12.2, singly subst ituted analogues of each peptide were tested for their activity in lys is assays. Differences were observed between the two epitopes with res pect to permissible residue substitutions at each peptide position fro m P3 to P8; marked differences were evident at P3 and at P8. The resul ts obtained suggest that this TCR forms critical contacts with atoms a t peptide positions P3 and P5 of p1049/A2.1 and at P5 and P8 of p1058/ D-b, and that TCR cross-recognition of these ligands is a function of both shared and complex-specific contacts made with each epitope. Thes e findings further highlight the versatile reactivity that may be show n by a single TCR and suggest a basis for the recognition of peptide l igands sharing only a limited set of structural features.