A conformation- and avidity-based proofreading mechanism for the TCR–CD3 complex

During antigen recognition, T cells show high sensitivity and specificity, and a wide dynamic range. Paradoxically, these characteristics are based on low-affinity receptor–ligand interactions [between the T-cell antigen receptor (TCR–CD3) complex and the antigen peptide bound to MHC]. Recent evidence indicates that the TCR–CD3 is expressed as multivalent complexes in the membrane of non-stimulated T cells and that conformational changes in the TCR–CD3 can be induced by strong but not weak agonists. Here, we propose a thermodynamic model whereby the specificity of the TCR–CD3–pMHC interaction is explained by its multivalent nature. We also propose that the free energy barriers involved in the change in conformation of the receptor impose a response threshold and determine the kinetic properties of recognition. Finally, we suggest that multivalent TCR–CD3s can amplify signals by spreading them from pMHC-engaged TCR–CD3s to unengaged complexes as a consequence of the cooperativity in the system.