Abstract
The molecular mechanism through which the interaction of a clonotypic αβ T-cell receptor (TCR) with a peptide-loaded major histocompatibility complex (p/MHC) leads to T-cell activation is not yet fully understood. Here we exploit a high-affinity TCR (B4.2.3) to examine the structural changes that accompany binding to its p/MHC ligand (P18-I10/H2-Dd). In addition to conformational changes in complementarity-determining regions (CDRs) of the TCR seen in comparison of unliganded and bound X-ray structures, NMR characterization of the TCR β-chain dynamics reveals significant chemical shift effects in sites removed from the MHC-binding site. Remodelling of electrostatic interactions near the Cβ H3 helix at the membrane-proximal face of the TCR, a region implicated in interactions with the CD3 co-receptor, suggests a possible role for an allosteric mechanism in TCR signalling. The contribution of these TCR residues to signal transduction is supported by mutagenesis and T-cell functional assays.
Highlights
The molecular mechanism through which the interaction of a clonotypic ab T-cell receptor (TCR) with a peptide-loaded major histocompatibility complex (p/MHC) leads to T-cell activation is not yet fully understood
As TCR affinities for p/MHC ligands span a wide range of KD from 0.5 to 4100 mM, this affinity is among the highest reported for a naturally occurring TCR
A fundamental question in T-cell immunity is the mechanism by which p/MHC engagement by the TCR is relayed to the associated CD3 subunits to initiate intracellular signalling
Summary
The molecular mechanism through which the interaction of a clonotypic ab T-cell receptor (TCR) with a peptide-loaded major histocompatibility complex (p/MHC) leads to T-cell activation is not yet fully understood. Remodelling of electrostatic interactions near the Cb H3 helix at the membrane-proximal face of the TCR, a region implicated in interactions with the CD3 co-receptor, suggests a possible role for an allosteric mechanism in TCR signalling. The contribution of these TCR residues to signal transduction is supported by mutagenesis and T-cell functional assays. Mutational and functional analyses suggest a critical role of these allosteric sites in signal transduction These results indicate a dynamic activation mechanism, where p/MHC recognition by the CDRs triggers conformational remodelling of interactions near the Cb H3 helix at the membrane-proximal face of the TCR
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