Mazza, C. et al. How much can a T-cell antigen receptor adapt to structurally distinct antigenic peptides? EMBO J. 26, 1972-1983

Centre d'Immunologie de Marseille-Luminy, Université de la Méditerrannée, 13288 Marseille Cedex 09, France.
The EMBO Journal (Impact Factor: 10.43). 05/2007; 26(7):1972-83. DOI: 10.1038/sj.emboj.7601605
Source: PubMed


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.

Download full-text


Available from: Nathalie Auphan-Anezin
  • Source
    • "The aim of the current study is to analyze in detail the features of the peptide-MHC complex, particularly the local flexibility of the binding cleft and the emerging peptide interaction networks, because this information is an indirect measure of the TCR affinity. The three-stage connection between peptide-MHC dynamical features, T cell affinity and activation potency is quite complex [7], [8] but, importantly, the most accepted TCR binding models [9], [10], [11], [12], [13] are based on a reciprocal conformational plasticity of both TCR and peptide-MHC, thus requiring a certain degree of peptide-MHC flexibility for a successful TCR recognition and then a conformational adjustment upon TCR binding [14], [15]. Recently the issue was investigated by many groups, in particular some authors [16], [17] provided important evidences, both computational and experimental, supporting a direct link between MHC protein flexibility – ‘floppy state’ – and enhanced peptide loading capabilities, with or without the help of an ancillary peptide loading enhancer protein called DM. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sardinia is a major Island in the Mediterranean with a high incidence of multiple sclerosis, a chronic autoimmune inflammatory disease of the central nervous system. Disease susceptibility in Sardinian population has been associated with five alleles of major histocompatibility complex (MHC) class II DRB1 gene. We performed 120 ns of molecular dynamics simulation on one predisposing and one protective alleles, unbound and in complex with the two relevant peptides: Myelin Basic Protein and Epstein Barr Virus derived peptide. In particular we focused on the MHC peptide binding groove dynamics. The predisposing allele was found to form a stable complex with both the peptides, while the protective allele displayed stability only when bound with myelin peptide. The local flexibility of the MHC was probed dividing the binding groove into four compartments covering the well known peptide anchoring pockets. The predisposing allele in the first half cleft exhibits a narrower and more rigid groove conformatio
    Full-text · Article · Mar 2013 · PLoS ONE
  • Source
    • "Although we know that peptides have different potencies to activate TCR signaling, we do not know if peptide cross-reactivity is achieved through a single docking footprint or if a range of MHC docking modes exist that would have disparate impacts on signaling induced by each peptide (Felix et al., 2007; Yin and Mariuzza, 2009). Although cross-reactive TCR complexes so far have shown similar docking modes (Mazza et al., 2007), in many cases the peptides shared key TCR contact residues (Ding et al., 1999; Macdonald et al., 2009; Mazza et al., 2007), leaving open the question of how sequences of unrelated peptides are accommodated by the TCR. "
    [Show abstract] [Hide abstract]
    ABSTRACT: T cell receptor (TCR) engagement of peptide-major histocompatibility complex (pMHC) is essential to adaptive immunity, but it is unknown whether TCR signaling responses are influenced by the binding topology of the TCR-peptide-MHC complex. We developed yeast-displayed pMHC libraries that enabled us to identify new peptide sequences reactive with a single TCR. Structural analysis showed that four peptides bound to the TCR with distinct 3D and 2D affinities using entirely different binding chemistries. Three of the peptides that shared a common docking mode, where key TCR-MHC germline interactions are preserved, induced TCR signaling. The fourth peptide failed to induce signaling and was recognized in a substantially different TCR-MHC binding mode that apparently exceeded geometric tolerances compatible with signaling. We suggest that the stereotypical TCR-MHC docking paradigm evolved from productive signaling geometries and that TCR signaling can be modulated by peptides that are recognized in alternative TCR-pMHC binding orientations.
    Full-text · Article · Nov 2011 · Immunity
  • Source
    • "We propose that the explanation of the observed results originates from the complex geometry of the recognition bridges that have to form (Fig. 4A) [11], [26], [42], [43]. To recognize a given pMHC, a TCR has to contact both the MHC and the peptide in a very finely controlled way on a restricted set of amino-acids. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The rupture forces and adhesion frequencies of single recognition complexes between an affinity selected peptide/MHC complex and a TCR at a murine hybridoma surface were measured using Atomic Force Microscopy. When the CD8 coreceptor is absent, the adhesion frequency depends on the nature of the peptide but the rupture force does not. When CD8 is present, no effect of the nature of the peptide is observed. CD8 is proposed to act as a time and distance lock, enabling the shorter TCR molecule to bridge the pMHC and have time to finely read the peptide. Ultimately, such experiments could help the dissection of the sequential steps by which the TCR reads the peptide/MHC complex in order to control T cell activation.
    Preview · Article · Jul 2011 · PLoS ONE
Show more