Volume 35, No 4, Apr 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 4, April 2025: 265-283   |  Open Access

ORIGINAL ARTICLES

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

Rui Qin^1,† , Yong Zhang^2,3,† , Jiawei Shi^4,† , Peng Wu^5,† , Chenyi An⁶ , Zhenhai Li⁷ , Nuo Liu^8,9 , Ziyan Wan^8,9 , Ting Hua^8,9 , Xiaolong Li^8,9 , Jizhong Lou^2,3,* , Weiwei Yin^4,* , Wei Chen^1,10,11,*

¹Department of Cardiology of the Second Affiliated Hospital and Department of Cell Biology, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, Zhejiang, China
²State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
³University of Chinese Academy of Sciences, Beijing, China
⁴Key Laboratory for Biomedical Engineering of the Ministry of Education, and Zhejiang Provincial Key Laboratory of Cardio-Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, and College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, Zhejiang, China
⁵Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
⁶School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou, China
⁷Shanghai Key Laboratory of Mechanics in Energy Engineering, Shanghai Institute of Applied Mathematics and Mechanics, School of Mechanics and Engineering Science, Shanghai University, Shanghai, China
⁸Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
⁹National Key Laboratory of Immune Response and Immunotherapy & MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
¹⁰State Key Laboratory of Transvascular Implantation Devices, Hangzhou, Zhejiang, China
¹¹MOE Frontier Science Center for Brain Science and Brain-machine Integration, Zhejiang University, Hangzhou, Zhejiang, China
^†These authors contributed equally: Rui Qin, Yong Zhang, Jiawei Shi, Peng Wu
Correspondence: Jizhong Lou(jlou@ibp.ac.cn)Weiwei Yin(wwyin@zju.edu.cn)Wei Chen(jackweichen@zju.edu.cn)

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 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.

https://doi.org/10.1038/s41422-025-01077-9

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