Predictable TCR antigen recognition based on peptide scans leads to the identification of agonist ligands with no sequence homology

The potential of CD4+ T cells for crossrecognition of self and foreign antigens has important implications for the understanding of thymic selection, lymphocyte survival, and the occurrence of autoimmune diseases. Here, we define the extensive flexibility of antigen recognition for three human CD4+ autoreactive T cell clones (TCC) by using ligands with single and multiple arnino acid (aa) substitutions. Our results demonstrate that the spectrum of tolerated ligands and the resulting stimulatory potency of peptides for a TCC can be predicted by the relative contributions of each aa. Using this approach, we have identified a stimulatory ligand not sharing a single aa in corresponding positions with the antigen used to establish the TCC. These results argue for an independent contribution of each aa in the peptide sequence to the affinity of the TCR for the ligand.