Related Experiment Video

Updated: Oct 28, 2025

A TIRF Microscopy Technique for Real-time, Simultaneous Imaging of the TCR and its Associated Signaling Proteins
16:10

A TIRF Microscopy Technique for Real-time, Simultaneous Imaging of the TCR and its Associated Signaling Proteins

Published on: March 22, 2012

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

Anna-Lisa Lanz1, Giulia Masi1, Nicla Porciello1

  • 1T-cell signalling laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.

Cell Reports
|July 14, 2021
PubMed

Insights

T-cell receptor (TCR-CD3) signaling is clarified by identifying mutations that enhance peptide-MHC signaling. These mutations weaken TCR-CD3 interactions, revealing a key step in T-cell activation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • The precise mechanism of T-cell receptor (TCR-CD3) signaling activation remains incompletely understood.
  • Existing models do not fully explain how TCR-CD3 complex engagement with peptide-MHC (pMHC) leads to signal initiation.

Purpose of the Study:

  • To elucidate the early molecular events governing TCR-CD3 complex activation upon pMHC binding.
  • To identify specific structural changes within the TCR-CD3 complex that trigger downstream signaling.

Main Methods:

  • Biochemical assays to measure protein interactions and signaling events.
  • Molecular dynamics simulations to analyze structural dynamics of the TCR-CD3 complex.
  • Site-directed mutagenesis to probe the function of transmembrane regions.

Main Results:

  • Gain-of-function mutations in TCRβ or CD3ζ transmembrane regions enhance pMHC-induced signaling independently of ligand binding or clustering.
  • pMHC binding, even in soluble monovalent form, reduces TCRαβ cohesion with CD3ζ prior to CD3ζ phosphorylation.
  • Activating mutations and pMHC binding both lead to a loosening of the TCRαβ-CD3ζ interaction.

Conclusions:

  • pMHC binding directly induces allosteric changes in the TCR-CD3 complex, reconfiguring transmembrane interactions.
  • These dynamic structural changes, rather than just ligand binding, are sufficient to initiate TCR-CD3 signaling.
  • Modifications at the TCR-CD3 boundary may alter lipid interactions, licensing CD3ζ phosphorylation and subsequent signal propagation.
Keywords:
T cell activationT cell antigen receptoradaptive immunityallosteric mechanismmembrane signallingmolecular dynamics simulation

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