부산대학교 도서관

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. Synopsis: The T‐cell antigen receptor (TCR) needs to discriminate between low‐affinity self‐peptide MHC antigens (pMHCs) and higher affinity foreign pMHCs. This study shows that mechanical force likely impairs TCR discrimination, supporting a role for adhesion receptors in shielding the TCR/pMHC interaction from mechanical forces.A cell‐free assay is used to systematically measure the off‐rate of 13 different TCR/pMHC interactions under different applied forces.In contrast to studies using intact T cells, we found that applied force increased the off‐rate of high‐affinity TCR/pMHC interactions by more than it did for low‐affinity interactions.Structured‐based molecular dynamics simulations confirmed these experimental findings.A kinetic proofreading model incorporating the observed effects of mechanical forces predicts that reducing the force on the TCR/pMHC interaction improves antigen discrimination and sensitivity.The ability of CD2 and LFA‐1 to improve antigen discrimination and sensitivity supports a role for these adhesion receptors in force‐shielding the TCR/pMHC interaction. [ABSTRACT FROM AUTHOR]