中国科学技术大学陈威研究团队报道了TCR捕获键非线性控制CD8合作形成T细胞特异性。这一研究成果发表在2025年2月27日出版的国际学术期刊《细胞研究》上。

该课题组还开发了全面的力依赖TCR-pMHC动力学功能图，能够区分功能性和非功能性TCR-pMHC对，并识别有毒的交叉反应性TCRs。这些发现阐明了天然TCRs特异性的机械化学基础，并强调了CD8在靶向同源抗原中的关键作用。这项工作为工程TCRs提供了有价值的见解，增强了对非自身抗原的特异性和效力，特别是在癌症免疫治疗和感染性疾病治疗中的应用，同时最大限度地降低了自身抗原交叉反应的风险。

研究人员表示，自然进化的T细胞受体（TCRs）在动态生物力学调节下对自身抗原和非自身抗原的区分表现出非常高的特异性。相比之下，工程化的高亲和力TCRs往往失去这种特异性，导致与自身抗原的交叉反应性和脱靶毒性。造成这种差异的潜在机制尚不清楚。他们的研究表明，天然的TCRs利用机械力与同源抗原形成最佳的捕获键。该过程依赖于机械柔性的TCR-pMHC结合界面，该界面通过在MHC和CD8中力诱导的顺序构象变化，使力增强的CD8辅受体结合到MHC-α₁α₂结构域。相反，工程化的高亲和力TCRs与亲本TCRs的同源pMHCs形成刚性紧密结合的界面。这种刚性防止了最佳捕获键形成所需的力引起的构象变化。矛盾的是，这些高亲和力的TCRs可以与其亲本TCRs的非刺激性pMHCs形成适度的捕获键，导致脱靶交叉反应性和特异性降低。

附：英文原文

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

Author: 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

Issue&Volume: 2025-02-27

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 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.

DOI: 10.1038/s41422-025-01077-9

Source: https://www.nature.com/articles/s41422-025-01077-9