Mechanical Forces Impair Antigen Discrimination by Reducing Differences in T-cell Receptor/peptide-MHC Off-rates

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2022 Dec 9

PMID 36484367

Authors

Johannes Pettmann

Lama Awada

Bartosz Rozycki

Anna Huhn

Sara Faour

Mikhail Kutuzov

Laurent Limozin

Thomas R Weikl

P Anton van der Merwe

Philippe Robert

Omer Dushek

Affiliations

Soon will be listed here.

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 debated. Here, we measured the effect of mechanical force on the off-rate of multiple TCR/pMHC interactions. Unexpectedly, we found that lower-affinity TCR/pMHCs with faster solution off-rates were more resistant to mechanical force (weak slip or catch bonds) than higher-affinity interactions (strong slip bonds). This was confirmed by molecular dynamics 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 a role for the adhesion receptors CD2 and LFA-1 in force-shielding the TCR/pMHC interaction.

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