The T cell receptor (TCR) can interact with a spectrum of peptides as part of its ligand, Including the immunogenic peptide, variants of this peptide, and apparently unrelated peptides. The basis of this broad specificity for ligand was investigated by substitution analysis of a peptide antigen and functional testing using a B cell apoptosls assay. A peptide containing as few as 1 aa in common with this peptide could stimulate a specific T cell response. Two endogenous ligands, an agonist and a partial agonist, were readily Identified from a search of the SwissProt database, indicating that multiple endogenous ligands likely exist for a given T cell. These findings strongly support the concept that one TCR has the ability to interact productively with multiple different Iigands, and provide evidence that such ligands exist in the endogenous peptide repertoire.