Improved Peptide-Discrimination by Force-Induced Unbinding of T Cell Receptor from Peptide-MHC

Abstract

Cell surface receptors (CSRs) are transmembrane proteins that link the binding of an external stimulus to an intracellular signal. One example is the T cell receptor (TCR), which specifically binds to peptides presented by MHC (pMHC) on an antigen-presenting cell. Discrimination power of “good” versus “poor” ligands can be realized with kinetic proofreading, however, it fails when it comes to ligands with only marginal differences in their off-rates: even if the TCR response was a perfect step-function in time, stochastic ligand dissociation would ultimately limit the specificity. We show here that the specificity of antigen-recognition can be massively improved by putting the TCR-pMHC bond under load: while under no force the bond rupture probability decays exponential with time, force-induced bond rupture leads to much narrower probability distributions. We applied the theory originating from AFM pulling experiments on a variety of different pMHC, and find consistently that under a pulling rate the T cell is enabled with a means of improved ligand discrimination.