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.
Mazza
Catherine
C
Centre d'Immunologie de Marseille-Luminy, Université de la Méditerrannée, 13288 Marseille Cedex 09, France.
Auphan-Anezin
Nathalie
N
Gregoire
Claude
C
Guimezanes
Annick
A
Kellenberger
Christine
C
Roussel
Alain
A
Kearney
Alice
A
van der Merwe
P Anton
PA
Schmitt-Verhulst
Anne-Marie
AM
Malissen
Bernard
B
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
D000941:Antigens; D022801:Complementarity Determining Regions; D006183:H-2 Antigens; D008024:Ligands; D050505:Mutant Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine