Allosteric activation of T cell antigen receptor signalling by quaternary structure relaxation

SummaryThe mechanism of T cell antigen receptor (TCR-CD3) signalling remains elusive. Here, we identified mutations in the transmembrane region of TCRβ or CD3ζ that augmented pMHC-induced signalling, not explainable by enhanced ligand binding, receptor diffusion, clustering or co-receptor function. Using a novel biochemical assay and molecular dynamics simulation, we found that the gain-of-function mutations modified transmembrane interactions that reduced TCRαβ cohesion with CD3ζ, suggesting that agonist pMHC binding may induce similar effects. Consistently, tetramer pMHC binding to TCR-CD3 reduced TCRαβ cohesion with CD3ζ, prior to CD3ζ phosphorylation. Moreover, we found that soluble monovalent pMHC alone induced signalling and reduced TCRαβ cohesion with CD3ζ in membrane-bound or solubilised TCR-CD3. Our data provide compelling evidence that pMHC binding suffices to activate allosteric changes propagating from TCRαβ to the CD3 subunits that reconfigure interchain transmembrane region interactions. This could modify the arrangement of TCR-CD3 boundary lipids to licence CD3ζ phosphorylation and initiate signal propagation.