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

Abstract

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‐2Kbm8 major histocompatibility complex (MHC) molecule, and compared it with the structures of the BM3.3 TCR bound to H‐2Kb 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.