CUTTING EDGE - 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 cross-recognition of self and foreig n Ags has important implications for the understanding of thymic selec tion, lymphocyte survival, and the occurrence of autoimmune diseases. Here, we define the extensive flexibility of Ag recognition for three human CD4+ autoreactive T cell clones (TCC) by using ligands with sing le and multiple amino 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 influen ce of each aa, Using this approach, me have identified stimulatory Lig ands not sharing a single aa in corresponding positions with the Ag us ed to establish the TCC. These results argue for an independent contri bution of each aa in the peptide sequence to the affinity of the MHC/p eptide complex to the TCR.