The T-cell receptor (TCR) must discriminate between peptides bound to major histocompatibility complex proteins and yet it can be triggered even without ligands at close contacts characterized by local depletion of the phosphatase, CD45. Here, we use a quantitative treatment of signaling that incorporates moving-boundary passage time calculations and is reliant only upon receptor dwell-time at close contacts to reconcile the contradictory properties of TCR triggering. We validate the model by showing that signaling is inversely related to close contact growth-rate and sensitive to the local balance of kinase and phosphatase activities. The model predicts that the small size of close contacts imposed by cell topography, and their short duration owing to the destabilizing effects of, for example, the glycocalyx, crucially underpins ligand discrimination by T cells without recourse to classical proofreading schemes. Based on simple physical principles, therefore, our model accounts for the main features of TCR triggering.

A cell-topography based mechanism for ligand discrimination by the T-cell receptor