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Analysis of peptide residues interacting with MHC molecule or T cell receptor. Can a peptide bind in more than one way to the same MHC molecule?

It has generally been assumed implicitly that one can define amino acid residues of a T cell antigenic determinant peptide that interact with the MHC molecule, i.e., residues that form the "agretope." However, if the same peptide can be seen in different conformations or orientations in the same MHC molecule by different T cells, then we would predict that some residues would appear to interact with the TCR of one T cell clone but with the MHC molecule as the peptide is seen by another T cell clone. To test this hypothesis, we synthesized 36 analogue peptides of an immunogenic fragment (P133-146) of sperm whale myoglobin with three different substitutions for each of 12 amino-acid residues and analyzed the role of each residue for I-Ed-binding and for activation of two Th clones, 14.1 and 14.5, specific for the peptide. The two T cell clones showed slightly different fine specificity from each other in that the truncated peptide P136-144 could stimulate 14.5 but not 14.1. The binding activity of nonstimulatory analogues to the I-Ed molecule was measured by functional inhibition analyses using truncated wild-type peptides as stimulators and nonstimulatory analogues as inhibitors. Paradoxical results were obtained that could not be explained by the peptide binding in a single way to the same I-Ed molecule. Some residues appeared to reciprocally reverse their roles for binding to I-Ed vs binding to the TCR when assessed using T-cell clone 14.5 compared to clone 14.1. These results fit the prediction of the above hypothesis and indicate the possibility that the same peptide, P133-146, can bind in more than one way to the same Ia molecule. The T cell clones, 14.1 and 14.5, appear to recognize different P133-146-I-Ed complexes in which the peptide is bound differently. Moreover, a given residue may not have a unique function of always interacting with the MHC molecule or TCR, but may change from one role to the other as it is presented to different T cells.