MOLECULAR-BASIS FOR THE RECOGNITION OF 2 STRUCTURALLY DIFFERENT MAJORHISTOCOMPATIBILITY COMPLEX PEPTIDE COMPLEXES BY A SINGLE T-CELL RECEPTOR

2C is a typical alloreactive cytotoxic T lymphocyte clone that recogni zes two different ligands, These ligands are adducts of the allo-major histocompatibility complex (MHC) molecule H-2L(d) and an endogenous o ctapeptide, and of the self-MHC molecule H-2K(b) and another peptide, MHC-binding and T-cell assays with synthetic peptides in combination w ith molecular modeling studies were employed to analyze the structural basis for this crossreactivity. The molecular surfaces of the two com plexes differ greatly in densities and distributions of positive and n egative charges, However, modifications of the peptides that increase similarity decrease the capacities of the resulting MHC peptide comple xes to induce T-cell responses, Moreover, the roles of the peptides in ligand recognition are different for self- and allo-MHC-restricted T- cell responses, The self-MHC-restricted T-cell responses were finely t uned to recognition of the peptide, The allo-MHC-restricted responses, on the other hand, largely ignore modifications of the peptide. The r esults strongly suggest that adaptation of the T-cell receptor to the different ligand structures, rather than molecular mimicry by the liga nds, is the basis for the crossreactivity of 2C, This conclusion has i mportant implications for T-cell immunology and for the understanding of immunological disorders.