TCR catch bonds nonlinearly control CD8 cooperation to shape T cell specificity.

ABSTRACT: Naturally evolved T-cell receptors (TCRs) exhibit remarkably high specificity in discriminating non-self antigens from self-antigens under dynamic biomechanical modulation. In contrast, engineered high-affinity TCRs often lose this specificity, leading to cross-reactivity with self-antigens and off-target toxicity. The underlying mechanism for this difference remains unclear. Our study reveals that natural TCRs exploit mechanical force to form optimal catch bonds with their cognate antigens. This process relies on a mechanically flexible TCR-pMHC binding interface, which enables force-enhanced CD8 coreceptor binding to MHC-α₁α₂ domains through sequential conformational changes induced by force in both the MHC and CD8. Conversely, engineered high-affinity TCRs create r

SUBMITTER: Qin R 

PROVIDER: S-EPMC11958657 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature