Mechanical forces impair antigen discrimination by reducing differences in T cell receptor off-rates

Abstract

T cells use their T cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity foreign peptide major-histocompatibility-complexes (pMHCs) based on the TCR/pMHC off-rate. It is now appreciated that T cells generate mechanical forces during this process but how force impacts the TCR/pMHC off-rate remains unclear. Here, we measured the effect of mechanical force on the off-rate of multiple TCR/pMHC interactions. Unexpectedly, we found that lower-affinity pMHCs with faster solution off-rates were more resistant to mechanical force (weak slip or catch bonds) than higher-affinity interactions (strong slip bonds), and this was confirmed by molecular dynamic simulations. Consistent with these findings, we show that the best characterized catch-bond, involving the OT-I TCR, has a low affinity and an exceptionally fast solution off-rate. Our findings imply that reducing forces on the TCR/pMHC interaction improves antigen discrimination and we suggest this new force-shielding role for the adhesion receptors CD2 and LFA-1.

A Microfluidic Strategy to Capture Antigen‐Specific High‐Affinity B Cells

“…We assumed a first-order process for cell detachment: 10) are the number of cells that bind at least t b and 10 s, respectively, Thus, the off-rate is simply the slope of the line graph between fraction of bound cells and their bound lifetime, which is also referred to as survival curves. [26,27] Data fits were weighted by the fraction of bound cells. The force-dependent k off is related to force independent k 0 off by the Bell model, [28] k off ¼ k 0 off e x β F=K B T , where x β is reactive compliance of the intermolecular bond, F is the force applied on the bond, and K B is Boltzmann's constant.…”