Catch bond models may explain how force amplifies TCR signaling and antigen discrimination

Abstract

Central to T cell biology, the TCR integrates forces in its triggering process upon interaction with pMHC. Phenotypically, forces elicit TCR catch–slip bonds with strong pMHCs but slip–only bonds with weak pMHCs. While such correlation is generally observed, the quantitative bond pattern and degree of catchiness vary. We developed two models based on the structure, elastic properties, and force–induced conformational changes of the TCR–pMHC–I/II complexes to derive from their bond characteristics more intrinsic parameters that underlie structural mechanisms, predict T cell signaling, and discriminate antigens. Applying the models to all published 48 datasets of 11 TCRs and their mutants interacting with corresponding pMHCs revealed the ability for structural and physical parameters to quantitatively integrate and classify a broad range of bond behaviors and biological activities. The extensive comparisons between theory and experiment allowed us to validate the models and identify specific conformational changes that control bond profiles, thereby providing structural insights into the inner workings of the TCR mechanosensing machinery and explaining why and how force amplifies TCR signaling and antigen discrimination.

Topology of molecular deformations induces triphasic catch bonding in selectin-ligand bonds

“…MD simulation of protein-ligand unbinding is a notoriously difficult problem [52], as typical bond lifetimes (often ∼ 1s) are vastly longer than feasible simulation times (typically ≲1 ms). To overcome this issue, steered MD simulations, in which artificially high forces are used to increase unbinding rates, are often employed to study catch bonds [19,[36][37][38]. However, our results show that the transition state of catch bonds can be very sensitive to force; indeed, catch behavior is generated by this sensitivity.…”

“…T-cell receptor (TCR) binding to pMHC is one exciting system where catch bonding has been observed. Intriguingly, force-induced deformations of TCRs have been suggested to play a key role in T-cell activation [38]. However, such a model would necessitate moving beyond the 2-dimensional framework used in this work.…”

“…Furthermore, this brings into question the suitability of steered molecular dynamics (SMD) to study protein-ligand unbinding. Though widely used to study catch bonding [19,[36][37][38], the artificially strong forces used in SMD may drastically alter the unbinding dynamics.…”

ABCD of IA: A multi-scale agent-based model of T cell activation in inflammatory arthritis

“…In particular, the acquisition of catch bonds within the TCR-pMHC interface has been shown to be a parameter that can permit differentiation between agonist from nonagonist ligands in the context of high-affinity TCR-pMHC interactions. [63][64][65] Prior work has developed models in the context of known peptides (e.g., from virus and cancer anti-gens) and TCR clones that are responsive (or not responsive) to pMHC. While these analyses do not include inflammatory arthritis (IA), we acknowledge that it is plausible that catch bonds influence T cell activation in IA.…”

WASP facilitates tumor mechanosensitivity in T lymphocytes

“…Despite mounting evidence that the mechanical context of antigen presentation dictates T cell activation and subsequent immune response 7,13 , the mechanisms by which mechanical forces at the synapse are sensed and transduced within the CTLs are not completely clear. Recent studies have shown that TCR can participate in the mechanosensitive activation of T cells by utilizing forces for improving the lifetime of the bond with the MHC-antigen 8,12,16,17 and by involving as yet uncharacterized downstream mechanisms at the cell surface resulting in mechanosensitivity [18][19][20] . Still, the molecular pathways downstream of TCR that consolidate and transduce the mechanical information to the cell interior remain unclear.…”