Forces in T Cell Antigen Recognition

Abstract

There are strong indications that mechanical forces are particularly relevant in immune recognition. For the immune system, the enormous variety of antigenic ligands imposes a fundamental challenge to the discriminative power; the mechanism for discriminating between activating and non-activating ligands has remained enigmatic.In a recent theoretical study we showed how forces alters the potency for receptor ligand discrimination by orders of magnitudes(1). For the T cell receptor, which specifically binds to peptides presented by MHC on an antigen-presenting cell, discrimination can be realized with kinetic proofreading, which fails when ligands have only marginal differences in their off-rates. We showed, however, 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 exponentially with time, force-induced bond rupture leads to much narrower distributions.Here, we present cellular traction force microscopy data to measure forces involved during T cell activation. Hydrogels were prepared with variable stiffness. Fluorescent beads carrying CD3 antibodies were immobilized onto the top layer of the hydrogel. Forces are read out by measuring the fluorescent bead movement throughout T cell attachment and activation. The bead movement was directly correlated to forces applied to the antibodies immobilized on the beads. Moreover, discrimination between lateral and transversal applied forces was possible by tracking the beads' positions in 3D.1.Klotzsch, E., and G.J. Schutz. 2013. Improved Ligand Discrimination by Force-Induced Unbinding of the T Cell Receptor from Peptide-MHC. Biophysj. 104: 1670-1675.