T cell receptors: affinities, cross-reactivities, and a conformer model

Based on findings with the T cell receptor from mouse CTL clone 2C, and other TCRs, we propose a model that could account for degeneracy of T cell recognition. This "conformer model" holds that a single TCR exists in multiple conformations that are in equilibrium. The model is consistent with (1) the characterization of multiple ligands that bind to the 2C TCR, and other TCRs, (2) the binding properties and predicted structural features of various 2C TCR mutants, including higher affinity variants isolated by directed evolution, and (3) the three-dimensional structures of TCRs and antibodies, with emphasis on the conformational diversity exhibited by proteins with the same primary amino acid sequence. We propose that the advantages of multiple conformers (e.g. ability of a single T cell to recognize many different ligands) outweigh the disadvantages (e.g. lower TCR affinity and possibly T cell sensitivity; detrimental cross-reactivity with structurally unrelated self-ligands).