Allopeptide-specific T cell reactivity altered by peptide analogs.

Abstract

Recent evidence indicates that indirect allorecognition plays a key role in initiating and sustaining graft rejection. This self-restricted T cell response is generally limited to a restricted set of dominant immunogenic peptides derived from allogeneic HLA molecules. Here, we have examined whether peptide analogues of the dominant determinant of HLA-DRbeta1*0101 molecule (peptide DR1/22-35), recognized in the context of HLA-DRbeta1*1101 protein, are able to modulate the T cell response against the wild-type peptide Ag. The peptide analogues were generated by introducing single amino acid substitutions at putative MHC and TCR contact positions. Two analogues, 25R/A and 28E/Q, which bound to soluble DR11 protein, but did not stimulate an anti-DR1-specific T cell clone, inhibited the response of the clone to the wild-type peptide by TCR antagonism. Analogs 25R/A and 28E/Q were also able to inhibit the differentiation of Th precursors specific for peptide DR1/22-35. Two other peptides, 26L/I and 27L/V, acted as powerful TCR agonists, inducing a higher proliferative response of the DR1-specific T cell clone, compared with the wild-type peptide. At high concentrations, these peptides induced hyporesponsiveness of TCC-ZL36 in a manner similar to the wild-type peptide. Taken together, the results of this study indicate that specific suppression of indirect allorecognition can be achieved by using structural variants of the dominant allodeterminant.