TCR Mechanobiology: Torques and Tunable Structures Linked to Early T Cell Signaling

Abstract

Mechanotransduction is a basis for receptor signaling in many biological systems. Recent data based upon optical tweezer experiments suggest that the TCR is an anisotropic mechanosensor, converting mechanical energy into biochemical signals upon specific peptide-MHC complex (pMHC) ligation. Tangential force applied along the pseudo-twofold symmetry axis of the TCR complex post-ligation results in the αβ heterodimer exerting torque on the CD3 heterodimers as a consequence of molecular movement at the T cell–APC interface. Accompanying TCR quaternary change likely fosters signaling via the lipid bilayer predicated on the magnitude and direction of the TCR–pMHC force. TCR glycans may modulate quaternary change, thereby altering signaling outcome as might the redox state of the CxxC motifs located proximal to the TM segments in the heterodimeric CD3 subunits. Predicted alterations in TCR TM segments and surrounding lipid will convert ectodomain ligation into the earliest intracellular signaling events.

Pre-T Cell Receptors (Pre-TCRs) Leverage Vβ Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands

“…Direct evidence that the TCR acts as a mechanosensor was experimentally shown through optical tweezer-based measurements that presented pMHC-coated beads to surface-bound ␣␤TCRs, where mere binding without force was insufficient for triggering, but tangential force resulted in T cell activation, leading us to propose a mechanical model for signal transduction (17). The concept of bond strengthening with force reconciles the discrepancy between the exquisite sensitivity and specificity of the ␣␤TCR on the one hand and its low affinity for ligand in the absence of physical load on the other hand (17)(18)(19)(20). A nonlinear response of the ␣␤TCR-pMHC bond was recently shown in biomembrane force probe and optical trap assays where single molecule interactions are probed (21,22).…”

Mechanosensing drives acuity of αβ T-cell recognition

“…Experiments with the same beads but force application normal to the cell surface did not lead to triggering. How T cells might use mechanical force and direction for triggering was conceptually proposed to involve nonlinear bonding kinetic mechanisms, including conformational change allostery and bond strengthening (32). This paradoxical extension of αβ TCR-pMHC-bond lifetime under force, so-called catch bond behavior, was then observed experimentally (19,33).…”

Lipid-dependent conformational dynamics underlie the functional versatility of T-cell receptor

“…Moreover, mutating CD3ε stalk region to prevent outside-in conformational transition leads to impaired TCR signaling [18,19,37]. On the other hand, mechanical force generated after T cell-APC conjugation might also affect the binding kinetics between CD3 cytoplasmic domains and the membrane [42,44]. Either allosteric regulation or force-induced movement should be dependent on the binding kinetics between TCR and pMHC and can cause antigen-specific conformational change to initiate TCR signaling.…”

“…Mutation of a Cys residue in the CD3ε stalk region to prevent the outside-in conformational transition leads to the blockade of αβ T cell development and impaired peripheral T cell function due to abnormal pre-TCR and TCR signaling [18,19,37]. Fourth, mechanical force has been shown to be critical for TCR signaling and might directly cause CD3 conformational change [2,[38][39][40][41][42][43][44]. These studies highlight the importance of conformational change in TCR triggering.…”