How much can a T‐cell antigen receptor adapt to structurally distinct antigenic peptides?

Binding degeneracy is thought to constitute a fundamental property of the T‐cell antigen receptor (TCR), yet its structural basis is poorly understood. We determined the crystal structure of a complex involving the BM3.3 TCR and a peptide (pBM8) bound to the H‐2K bm8 major histocompatibility complex (MHC) molecule, and compared it with the structures of the BM3.3 TCR bound to H‐2K b molecules loaded with two peptides that had a minimal level of primary sequence identity with pBM8. Our findings provide a refined structural view of the basis of BM3.3 TCR cross‐reactivity and a structural explanation for the long‐standing paradox that a TCR antigen‐binding site can be both specific and degenerate. We also measured the thermodynamic features and biological penalties that incurred during cross‐recognition. Our data illustrate the difficulty for a given TCR in adapting to distinct peptide‐MHC surfaces while still maintaining affinities that result in functional in vivo responses. Therefore, when induction of protective effector T cells is used as the ultimate criteria for adaptive immunity, TCRs are probably much less degenerate than initially assumed.