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.

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    • "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. "
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    • "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. "
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