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The mechanism of T cell antigen receptor (TCR-CD3) signalling remains unknown almost four decades after its discovery. We have identified mutations in the transmembrane region of TCR-beta or CD3-zeta that augment pMHC-induced signalling, not explicable by enhanced ligand binding, lateral diffusion, clustering or co-receptor function. Using a biochemical assay and molecular dynamics simulation, we demonstrate that the gain-of-function mutations loosen interaction between TCR-alpha/beta
and CD3-zeta. Similar to the activating mutations, pMHC binding reduces TCR-alpha/beta cohesion with CD3-zeta. This event occurs prior to CD3-zeta phosphorylation and at 0 ºC. Moreover, we have shown that soluble monovalent pMHC alone induces signalling and reduces
TCR-alpha/beta cohesion with CD3-zeta in membrane-bound or solubilised TCR-CD3. These data, together with recent NMR data, compellingly demonstrate that pMHC binding suffices to activate allosteric changes propagating from TCR-alpha/beta to the CD3 subunits, reconfiguring
interchain transmembrane region packing. These dynamic modifications could change the arrangement of TCR-CD3 boundary lipids to licence CD3-zeta phosphorylation and initiate T-cell activation.
Oreste Acuto is Professor of Molecular Cell Signalling and Head of T Cell Signalling Laboratory at Sir William Dunn School of Pathology, University of Oxford since 2006.
Prof. Acuto’s research has been dedicated to the understanding of the molecular basis of T cell
activation since the beginning of his career.
He was among the first to identify and define the human T cell receptor (TCR) and to discover that the TCR α and β subunits possess variable and constant regions. He has studied in detail how the TCR signal transduction is fine-tuned through the tyrosine kinases Lck and Zap-70, and discovered the Themis molecule, describing its role in the modulation of TCR-CD3 signalling and positive selection.
His most recent work describes the first molecular event that activates TCR-CD3 signal transduction.
Professor Acuto is author of more than 170 papers.