T cell receptors, mechanosensors, catch bonds and immunotherapy

T-cell based immunity is mediated through specific T cell receptor (TCR) recognition of a small antigenic peptide in complex with a host immune molecule, major histocompatibility complex (pMHC). The interaction of a TCR and its pMHC ligand is generally quite weak, degenerate and biophysically unfavorable. Yet, the resulting immune response is extremely effective, being both sensitive and specific. Recent observations indicate that the TCR is an anisotropic mechanosensor. The force sensed by TCR's recognition module is transmitted to the non-covalently associated signal transduction module. Multiple biophysical methods reveal that the molecular mechanism for TCR-pMHC interaction under force required to induce T cell signaling is linked to "catch bond" formation between a TCR and its cognate ligand pMHC. This kind of dynamic non-covalent bond actually increases the bond lifetime by deforming the molecule to make the interaction lock tighter. The key observation is that the more stimulatory the antigenic peptide, the more pronounced the catch bond and immune response. By contrast, an unrelated, non-antigenic peptide presented by the same MHC molecule does not form a catch bond, instead manifesting a slip bond associated with rapid TCR-pMHC dissociation. In summary, a weak interaction between a TCR and agonist ligand will be dramatically amplified by a catch bond under physical load generated by cell movement during immune surveillance. These new biophysical concepts, TCR mechanosensor and dynamic catch bond formation, begin to reveal how bioforces tune T cell signaling and should be potentially enlightening for immunotherapy design against cancers.