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Cited by 35

The DOI matches its Crossref record; 80 of the 80 references it cites were found in a registry or an index.

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

Qin, Rui, Zhang, Yong, Shi, Jiawei, Wu, Peng, An, Chenyi, Li, Zhenhai, Liu, Nuo, Wan, Ziyan, Hua, Ting, Li, Xiaolong, Lou, Jizhong, Yin, Weiwei, Chen, Wei·2025·Cell Research
DOI 10.1038/s41422-025-01077-9
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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-α 1 α 2 domains through sequential conformational changes induced by force in both the MHC and CD8. Conversely, engineered high-affinity TCRs create rigid, tightly bound interfaces with cognate pMHCs of their parental TCRs. This rigidity prevents the force-induced conformational changes necessary for optimal catch-bond formation. Paradoxically, these high-affinity TCRs can form moderate catch bonds with non-stimulatory pMHCs of their parental TCRs, leading to off-target cross-reactivity and reduced specificity. We have also developed comprehensive force-dependent TCR–pMHC kinetics-function maps capable of distinguishing functional and non-functional TCR–pMHC pairs and identifying toxic, cross-reactive TCRs. These findings elucidate the mechano-chemical basis of the specificity of natural TCRs and highlight the critical role of CD8 in targeting cognate antigens. This work provides valuable insights for engineering TCRs with enhanced specificity and potency against non-self antigens, particularly for applications in cancer immunotherapy and infectious disease treatment, while minimizing the risk of self-antigen cross-reactivity.

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Metadata

Authors
Qin, R., Zhang, Y., Shi, J., Wu, P., An, C., Li, Z., Liu, N., Wan, Z., Hua, T., Li, X., Lou, J., Yin, W., & Chen, W.
Venue
Cell Research
Publisher
Springer Science and Business Media LLC
Published
2025-02-27
Volume
35
Issue
4
Pages
265-283
ISSN
1748-7838
DOI
10.1038/s41422-025-01077-9
Cited by
35
References
80
Language
en
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