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

The mechanism of T cell antigen receptor (TCR-CD3) signalling remains elusive. Here, we identified mutations in the transmembrane region of TCR{beta} or CD3{zeta} 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 TCR{beta} cohesion with CD3{zeta}, suggesting that agonist pMHC binding may induce similar effects. Consistently, tetramer pMHC binding to TCR-CD3 reduced TCR{beta} cohesion with CD3{zeta}, prior to CD3{zeta} phosphorylation. Moreover, we found that soluble monovalent pMHC alone induced signalling and reduced TCR{beta} cohesion with CD3{zeta} in membrane-bound or solubilised TCR-CD3. Our data provide compelling evidence that pMHC binding suffices to activate allosteric changes propagating from TCR{beta} to the CD3 subunits that reconfigure interchain transmembrane region interactions. This could modify the arrangement of TCR-CD3 boundary lipids to licence CD3{zeta} phosphorylation and initiate signal propagation.