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 CD3 epsilon cytoplasmic tail as well as in the extracellular TCR beta 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 CD3 epsilon cytoplasmic tail leading to T-cell activation; (2) CD3 epsilon 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.
Rubin
B
B
Institut de Sciences et Technologies du Médicament de Toulouse (ISTMT), Toulouse, France. bent.rubin@istmt.cnrs.fr
Knibiehler
M
M
Gairin
J E
JE
D000494:Allosteric Regulation / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017252:CD3 Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D045604:Extracellular Fluid / Q000378:metabolism*; D007424:Intracellular Fluid / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D008024:Ligands; D016693:Receptors, Antigen, T-Cell, alpha-beta