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

Journal article

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.

Authors: Mazza, C; Auphan-Anezin, N; Gregoire, C; Guimezanes, A; Kellenberger, C

• Publication status: Published
• Journal: EMBO journal
• Volume: 26
• Issue: 7
• Pages: 1972-1983
• Publication date: 2007-04-01
• DOI: 10.1038/sj.emboj.7601605
• EISSN: 1460-2075
• ISSN: 0261-4189
• Language: English
• Keywords: Peptides; Tyrosine; H-2 Antigens; Mutant Proteins; Complementarity Determining Regions; Crystallography, X-Ray; Thermodynamics; Protein Structure, Secondary; Mice; Molecular Sequence Data; Receptors, Antigen, T-Cell; Models, Molecular; Animals; Antigens; Amino Acid Sequence; Ligands