Early T cell receptor signals globally modulate ligand:receptor affinities during antigen discrimination

Abstract

Significance Antigen discrimination by T cells is based on subtle differences in binding of the T cell receptor (TCR) for its peptide major histocompatibility complex (pMHC) ligand. While such binding characteristics are readily mapped with great precision in reconstituted biochemical systems, it is less clear how these interactions are affected in the live cell environment. Here we utilize single-molecule imaging to individually resolve all of the pMHC:TCR binding events in live T cells. The quantitative measurements reveal an active feedback mechanism that globally modulates the probability of pMHC:TCR binding throughout the cell–cell interface, without affecting the unbinding rate. The result is to increase the efficiency with which TCRs scan for antigen pMHC after the first few molecular encounters have occurred.