Allosteric Changes in the TCR/CD3 Structure Upon Interaction With Extra‐ or Intra‐cellular Ligands

T lymphocytes are activated by the interaction between the T‐cell antigen receptor (TCR) and peptides presented by major histocompatibility complex (MHC) molecules. The avidity of this TCR–pMHC interaction is very low. Therefore, several hypotheses have been put forward to explain how T cells become specifically activated despite this handicap: conformational change model, aggregation model, kinetic segregation model, sequential interaction model and permissive geometry model. In the present paper, we conducted experiments to distinguish between the TCR‐aggregation model and the TCR‐conformational change model. The results obtained using a TCR capture ELISA with Brij 98‐solubilized TCR molecules from normal or activated T cells showed that the ligand–TCR interaction causes structural changes in the CD3ε cytoplasmic tail as well as in the extracellular TCRβ FG loop region. Size‐fractionation experiments with Brij 98‐solubilized TCR/CD3/co‐receptor complexes from naïve or activated CD4 + or CD8 + T cells demonstrated that such complexes are found as either dimers or tetramers. No monomers or multimers were detected. We propose that: (1) ligand–TCR interaction results in conformational changes in the CD3ε cytoplasmic tail leading to T‐cell activation; (2) CD3ε cytoplasmic tail interaction with intracellular proteins may dissociate pMHC and co‐receptors (CD4 or CD8) from TCR/CD3 complexes, thus leading to the arrest of T‐cell activation; and (3) T‐cell activation appears to occur among dimers or tetramers of TCR/CD3/co‐receptor complexes interacting with self and non‐self (foreign) peptide‐MHC complexes.