Degenerate recognition of alloantigenic peptides on a positive- selecting class I molecule

The well-defined 2C T cell was used to investigate alloreactive degeneracy. A panel of class I molecules that are known ligands for the 2C TCR were sensitized with three known peptide ligands, p2Ca (LSPFPFDL), dEV-8 (EQYKFYSV), and SIYR-8 (SIYRYYGL). The peptide p2Ca was originally identified as the allopeptide seen in the L(d) class I molecule by 2C T cells, 2C recognizes the dEV-8 peptide as the ligand in the K(bm3) class I molecule, and SIYR-8 was recently identified as a peptide ligand for 2C in the context of the K(b) class I molecule. Strong recognition of all three Ag-presenting molecules occurred in the context of their respective allopeptides, but 2C recognized all three peptides to a measurable extent in the context of K(b). Molecular modeling of these K(b)/peptide complexes revealed a high degree of similarity between dEV-8 and SIYR-8, but very little conformational similarity of either of these peptides with p2Ca. Furthermore, the structural changes in the mutant K(bm3) binding site resulted in generalized changes in the conformation of each of five bound peptides compared with those of the same peptides bound to K(b). The finding that degenerate recognition occurs on K(b), the restriction element responsible for selecting 2C T cells, suggests a unique relationship between a TCR and the Ag-presenting molecule that mediates its positive selection.