Article
- The EMBO Journal (2007) 26, 1972 - 1983
- doi:10.1038/sj.emboj.7601605
Published online: 15 March 2007
Subject Categories:
How much can a T-cell antigen receptor adapt to structurally distinct antigenic peptides?
Catherine Mazza1,2,3, Nathalie Auphan-Anezin1,2,3, Claude Gregoire1,2,3, Annick Guimezanes1,2,3, Christine Kellenberger1,2,3, Alain Roussel4, Alice Kearney5, P Anton van der Merwe5, Anne-Marie Schmitt-Verhulst1,2,3 and Bernard Malissen1,2,3
- Centre d'Immunologie de Marseille-Luminy, Université de la Méditerrannée, Marseille Cedex 9, France
- INSERM, U631, Marseille Cedex 9, France
- CNRS, UMR6102, Marseille Cedex 9, France
- AFMB UMR6098 CNRS, Parc Scientifique de Luminy, Marseille, Cedex 09, France
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
Correspondence to:
Bernard Malissen, Centre d'Immunologie de Marseille-Luminy, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. Tel.: +33 491 269 418; Fax: +33 491 269 430; E-mail: bernardm@ciml.univ-mrs.fr
Received 9 June 2006; Accepted 23 January 2007
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.
Keywords:
- antigen recognition,
- binding degeneracy,
- T cell,
- TCR
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