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

• Published in: Scandinavian journal of immunology 2007-08, Vol.66 (2-3), p.228-237
• Main Authors: Rubin, B, Knibiehler, M, Gairin, J.E
• Format: Article
• Language: English
• Subjects: Allosteric Regulation - immunology; Amino Acid Sequence; Animals; Antibodies, Monoclonal - metabolism; CD3 Complex - chemistry; CD3 Complex - genetics; CD3 Complex - metabolism; Cell Line, Tumor; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Extracellular Fluid - metabolism; Intracellular Fluid - metabolism; Ligands; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Receptors, Antigen, T-Cell, alpha-beta - chemistry; Receptors, Antigen, T-Cell, alpha-beta - immunology; Receptors, Antigen, T-Cell, alpha-beta - metabolism
• ISSN: 0300-9475; 1365-3083
• DOI: 10.1111/j.1365-3083.2007.01979.x

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.