title: 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-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.affiliation: Centre d'Immunologie de Marseille-Luminy, Université de la Méditerrannée, 13288 Marseille Cedex 09, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mazza
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auphan-Anezin
authors.forename: Claude
authors.initials: C
authors.lastname: Gregoire
authors.forename: Annick
authors.initials: A
authors.lastname: Guimezanes
authors.forename: Christine
authors.initials: C
authors.lastname: Kellenberger
authors.forename: Alain
authors.initials: A
authors.lastname: Roussel
authors.forename: Alice
authors.initials: A
authors.lastname: Kearney
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Schmitt-Verhulst
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000737:chemistry* / Q000276:immunology*; D022801:Complementarity Determining Regions / Q000737:chemistry; D018360:Crystallography, X-Ray; D006183:H-2 Antigens / Q000276:immunology; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013816:Thermodynamics; D014443:Tyrosine
chemical_list: D000941:Antigens; D022801:Complementarity Determining Regions; D006183:H-2 Antigens; D008024:Ligands; D050505:Mutant Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine