Engagement with the TCR induces plasticity in antigenic ligands bound to MHC class I and CD1 molecules

Complementarity-determining regions (CDRs) of alpha beta T-cell receptors (TCRs) sense peptide-bound MHC (pMHC) complexes via chemical interactions, thereby mediating antigen specificity and MHC restriction. Flexible finger-like movement of CDR loops contributes to the establishment of optimal interactions with pMHCs. In contrast, peptide ligands captured in MHC molecules are considered more static because of the rigid hydrogen-bond network that stabilizes peptide ligands in the antigen-binding groove of MHC molecules. An array of crystal structures delineating pMHC complexes in TCR-docked and TCR-undocked forms is now available, which enables us to assess TCR engagement-induced conformational changes in peptide ligands. In this short review, we overview conformational changes in MHC class I-bound peptide ligands upon TCR docking, followed by those for CD1-bound glycolipid ligands. Finally, we analyze the co-crystal structure of the TCR:lipopeptide-bound MHC class I complex that we recently reported. We argue that TCR engagement-induced conformational changes markedly occur in lipopeptide ligands, which are essential for exposure of a primary T-cell epitope to TCRs. These conformational changes are affected by amino acid residues, such as glycine, that do not interact directly with TCRs. Thus, ligand recognition by specific TCRs involves not only T-cell epitopes but also non-epitopic amino acid residues. In light of their critical function, we propose to refer to these residues as non-epitopic residues affecting ligand plasticity and antigenicity (NR-PA). The plasticity shown by ligands after TCR engagement

Automated summary

Complementarity-determining regions (CDRs) of alpha beta T-cell receptors (TCRs) sense peptide-bound MHC (pMHC) complexes via chemical interactions, contributing to antigen specificity and MHC restriction. Conformational changes in peptide ligands occur upon TCR docking, affecting the exposure of T-cell epitopes. Ligand recognition by specific TCRs involves not only epitopic residues, but also non-epitopic residues affecting ligand plasticity and antigenicity (NR-PA).