小柯机器人

清华大学张永辉等研究人员合作发现，磷酸抗原粘合乳糜蛋白3A1和2A1激活Vγ9Vδ2 T细胞。2023年9月6日，《自然》杂志在线发表了这项成果。

研究人员展示了在人类和羊驼中，多种磷酸抗原（pAg）如何发挥“分子胶水”的作用，促进BTN3A1和结构相似的乳糜蛋白BTN2A1细胞内结构域之间的异构体结合。X射线晶体学研究显示，BTN3A1与pAg的接触形成了一个复合界面，可直接与BTN2A1结合，不同的pAg分子分别位于界面的中心，以不同的亲和力粘合乳糜蛋白。结构结果指导了诱变实验，从而破坏了细胞内BTN3A1-BTN2A1的结合，取消了pAg介导的Vγ9Vδ2 T细胞活化。

利用基于结构的分子动力学模拟、¹⁹F-NMR研究、嵌合受体工程和细胞间结合力的直接测量进行分析，揭示了pAg介导的BTN2A1关联如何以热力学上有利的方式驱动BTN3A1细胞内波动向外，从而使BTN3A1从BTN2A1外结构域推开，启动T细胞受体介导的γδ T细胞活化。在实践中，研究人员利用分子胶水模型进行免疫疗法设计，展示了开发人类γδ T细胞功能小分子激活剂和抑制剂的化学原理。

据了解，在癌症和感染中，病变细胞通过一个“由内而外”的信号传递过程递呈给人类Vγ9Vδ2 T细胞，在这个过程中，乳糜蛋白BTN3A1的胞内结构域感应到结构多样的pAg分子。

附：英文原文

Title: Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells

Author: Yuan, Linjie, Ma, Xianqiang, Yang, Yunyun, Qu, Yingying, Li, Xin, Zhu, Xiaoyu, Ma, Weiwei, Duan, Jianxin, Xue, Jing, Yang, Haoyu, Huang, Jian-Wen, Yi, Simin, Zhang, Mengting, Cai, Ningning, Zhang, Lin, Ding, Qingyang, Lai, Kecheng, Liu, Chang, Zhang, Lilan, Liu, Xinyi, Yao, Yirong, Zhou, Shuqi, Li, Xian, Shen, Panpan, Chang, Qing, Malwal, Satish R., He, Yuan, Li, Wenqi, Chen, Chunlai, Chen, Chun-Chi, Oldfield, Eric, Guo, Rey-Ting, Zhang, Yonghui

Issue&Volume: 2023-09-06

Abstract: In both cancer and infections, diseased cells are presented to human Vγ9Vδ2 T cells through an ‘inside out’ signalling process whereby structurally diverse phosphoantigen (pAg) molecules are sensed by the intracellular domain of butyrophilin BTN3A11–4. Here we show how—in both humans and alpaca—multiple pAgs function as ‘molecular glues’ to promote heteromeric association between the intracellular domains of BTN3A1 and the structurally similar butyrophilin BTN2A1. X-ray crystallography studies visualized that engagement of BTN3A1 with pAgs forms a composite interface for direct binding to BTN2A1, with various pAg molecules each positioned at the centre of the interface and gluing the butyrophilins with distinct affinities. Our structural insights guided mutagenesis experiments that led to disruption of the intracellular BTN3A1–BTN2A1 association, abolishing pAg-mediated Vγ9Vδ2 T cell activation. Analyses using structure-based molecular-dynamics simulations, 19F-NMR investigations, chimeric receptor engineering and direct measurement of intercellular binding force revealed how pAg-mediated BTN2A1 association drives BTN3A1 intracellular fluctuations outwards in a thermodynamically favourable manner, thereby enabling BTN3A1 to push off from the BTN2A1 ectodomain to initiate T cell receptor–mediated γδ T cell activation. Practically, we harnessed the molecular-glue model for immunotherapeutics design, demonstrating chemical principles for developing both small-molecule activators and inhibitors of human γδ T cell function. Phosphoantigen-mediated BTN2A1 association drives BTN3A1 intracellular fluctuations outwards in a thermodynamically favourable manner, thereby enabling BTN3A1 to push off from the BTN2A1 ectodomain to initiate T cell receptor–mediated γδ T cell activation.

DOI: 10.1038/s41586-023-06525-3

Source: https://www.nature.com/articles/s41586-023-06525-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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