Allopeptide-specific T cell reactivity altered by peptide analogs.
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.
Colovai
A I
AI
Department of Pathology, College of Physicians and Surgeons of Columbia University, New York 10032, USA.
Liu
Z
Z
Harris
P E
PE
Cortesini
R
R
Suciu-Foca
N
N
D000596:Amino Acids / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007109:Immunity / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000032:analysis* / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013491:Suppressor Factors, Immunologic / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000596:Amino Acids; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007519:Isoantigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D013491:Suppressor Factors, Immunologic