Antagonism of direct alloreactivity of an HLA-B27-specific CTL clone by altered peptide ligands of its natural epitope.
Antagonism of allospecific CTL by altered MHC ligands is a potential approach to specific immunomodulation of allogeneic T cell responses in acute graft rejection and graft-vs-host disease. In this study we have analyzed the capacity of peptide analogs of a natural HLA-B27-allospecific CTL epitope to antagonize direct alloreactivity. Alanine scanning demonstrated that positions 4, 5, and 7 of the peptide epitope were critical for allorecognition. A number of relatively conservative substitutions at each of these positions were then tested for their effect on allorecognition and antagonism. All substitutions at position 5 abrogated cytotoxicity. In contrast, a few changes at positions 4 and 7 were tolerated, indicating a limited flexibility of the allospecific CTL in recognition of peptide epitope variants. Most of the substitutions impairing cytotoxicity actually induced antagonism. However, whereas epitope variants with changes at positions 4 and 7 behaved as weak or intermediate antagonists, some of the variants with changes at position 5 antagonized CTL alloreactivity almost completely. The results in this study demonstrate for the first time that antagonism of direct class I-mediated alloreactivity can be achieved by variants of a natural allospecific peptide epitope.
García-Peydró
M
M
Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Cientificas), Universidad Autónoma de Madrid, Facultad de Ciencias, Cantoblanco, Madrid, Spain.
Paradela
A
A
Albar
J P
JP
Castro
J A
JA
D019943:Amino Acid Substitution / Q000276:immunology; D017951:Antigen Presentation; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000032:analysis / Q000276:immunology* / Q000378:metabolism*; D015796:HLA-B27 Antigen / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009842:Oligopeptides / Q000819:agonists / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*
D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen; D008024:Ligands; D009842:Oligopeptides