PT  - JOURNAL ARTICLE
AU  - Johannes Pettmann
AU  - Lama Awada
AU  - Bartosz Różycki
AU  - Anna Huhn
AU  - Sara Faour
AU  - Mikhail Kutuzov
AU  - Laurent Limozin
AU  - Thomas R. Weikl
AU  - P. Anton van der Merwe
AU  - Philippe Robert
AU  - Omer Dushek
TI  - Mechanical forces impair antigen discrimination by reducing differences in T cell receptor off-rates
AID  - 10.1101/2022.05.05.490751
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.05.05.490751
4099  - http://biorxiv.org/content/early/2022/05/05/2022.05.05.490751.short
4100  - http://biorxiv.org/content/early/2022/05/05/2022.05.05.490751.full
AB  - 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.One sentence summary Mechanical forces disproportionately accelerate the off-rates of higher-affinity antigens reducing T cell antigen discriminationCompeting Interest StatementThe authors have declared no competing interest.