Limited plasticity in the recognition of peptide epitope variants by an alloreactive CTL clone correlates directly with conservation of critical residues and inversely with peptide length

Although self-restricted T cells are peptide-specific and can distinguish a mong closely related ligands, they have some flexibility in the recognition of sequence variants of their natural peptide epitopes. Alloreactive cytot oxic T lymphocytes (CTL) can recognize specific peptides bound to the allo- major histocompatibility complex (MHC) molecule, but their plasticity in th e recognition of related peptide variants has not been properly defined. Th e anti-B*2705 alloreactive CTL 27S69 specifically recognizes a natural octa mer ligand of HLA-B*2705. In this study, we tested the recognition of a nes ted set of epitope variants by this CTL clone. Although none of these pepti des was recognized equally as the natural epitope, two of the peptide varia nts were recognized with only slightly decreased efficiency. Peptide sensit ization assays showed that CTL recognition of epitope variants correlated d irectly with conservation of two non-anchor residues that were critical for recognition of the natural epitope, and inversely with peptide length. Mol ecular modeling of the peptide variants complexed with B*2705 provided a ra tional explanation for their differential recognition. Location of the two critical peptide residues at the right three-dimensional space favored effi cient recognition by CTL 27S69. The negative effect of increasing peptide l ength on recognition was due to the bigger bulging surface between the two critical residues, which precluded for optimal interaction with the specifi c T-cell receptors (TCR). Our results demonstrate that an alloreactive CTL has a degree of plasticity in the recognition of peptide epitope variants t hat is comparable to that of peptide-specific self-restricted CTL, and defi ne the structural features determining crossreaction among related peptides .