Calculations show that T cell antigen discrimination requires multiple localized binding events (35.3)

Abstract

Abstract T cells of the adaptive immune system rapidly scan the surface of antigen-presenting-cells (APC) for foreign material, in the form of peptide-MHC, using their T cell receptors (TCR). T cell activation via TCR-pMHC binding is extremely sensitive (a single presented pMHC can elicit a transient response), specific (a single amino acid substitution on a presented peptide can dramatically alter the response), and the decision to respond (e.g. by forming an immune synapse) occurs rapidly. Mathematical modeling based on statistical distributions reveals that pMHC must be repeatedly sampled (by binding TCR) in order for the T cell to make the decision to respond (or not) reliably. We find that TCR clustering and coreceptors act to immobilize pMHC which ensures that multiple binding events arise from a given pMHC. Functional assays of 1G4 T cells binding to a panel of 17 altered-peptide-ligands (NY-ESO) are used to support predictions from the model. We propose that sensitive, specific, and rapid antigen discrimination that is reliable can take place between a single TCR/pMHC.