Fig. 1: Mechanical force-regulated TCR‒pMHC‒CD8 trimolecular interactions control TCR specificity.

A natural TCR forms catch bonds with R4-H2-K^b under an optimal force at 10 pN, which is further enhanced by the right participation of CD8 with molecule conformational changes and rotations. However, it forms slip bonds with L4-H2-K^b, and CD8 can no longer enhance this interaction. In contrast, an engineered high-affinity TCR forms catch bonds with both R4-H2-K^b and L4-H2-K^b with false contribution from CD8. The mechanical force-regulated TCR‒pMHC‒CD8 trimolecular interactions explain why engineered high-affinity TCRs have cross-reactivity with non-agonist peptides and induce false T cell responses.