清华大学张永辉团队的最新研究探明了亲丁酸蛋白多聚体的结构揭示了v - γ - 9v - δ2 T细胞受体激活的钳状机制。相关论文于2025年6月11日发表在《免疫学》杂志上。

利用低温电子显微镜，该研究组分析了单独结合微生物pAg HMBPP和与T细胞受体（TCR）复合的BTN多聚体的结构。这些结构表明，BTN3A1和BTN2A1通过细胞内B30.2结构域合作感知pAgs，而BTN3A2和BTN2A1在细胞外相互作用。TCR结合触发其构象变化，使BTN2A1能够横向结合vγ9链，BTN3A2能够与vδ2链的种系编码区和CDR3基序以及vγ9 CDR3进行顶端相互作用。他们的研究揭示了一种“钳状夹持”机制，BTN多聚体在TCR表面架起桥梁，以驱动激活。这些发现为γδ T细胞靶向免疫治疗建立了结构基础，而αβ T细胞策略依赖于主要组织相容性复合物介导的抗原呈递。

研究人员表示，Vγ9Vδ2 T细胞是主要的人类循环γδ T细胞亚群，通过跨膜亲丁酸蛋白（BTN3A1、BTN3A2和BTN2A1）识别磷酸化抗原（pAgs），对感染和肿瘤产生应答。

附：英文原文

Title: Structures of butyrophilin multimers reveal a plier-like mechanism for Vγ9Vδ2 T cell receptor activation

Author: Mai Zhang, Yiqing Wang, Ningning Cai, Yingying Qu, Xianqiang Ma, Jing Xue, Xiaorui Chen, Xueguang Zhang, Junyu Xiao, Yonghui Zhang

Issue&Volume: 2025-06-11

Abstract: Vγ9Vδ2 T cells, the major circulating human γδ T cell subset, respond to infections and tumors by recognizing phosphoantigens (pAgs) via transmembrane butyrophilins (BTN3A1, BTN3A2, and BTN2A1). Here, using cryoelectron microscopy, we resolved the structures of BTN multimers bound to the microbial pAg HMBPP alone and in complex with the T cell receptor (TCR). These structures reveal that BTN3A1 and BTN2A1 cooperate to sense pAgs through their intracellular B30.2 domains, whereas BTN3A2 and BTN2A1 interact extracellularly. TCR engagement triggers its conformational changes, allowing BTN2A1 to bind the Vγ9 chain laterally and BTN3A2 to interact apically with the Vδ2 chain’s germline-encoded regions and CDR3 motif, as well as the Vγ9 CDR3. Our study uncovers a “plier-like gripping” mechanism, where BTN multimers bridge the TCR surface to drive activation. These findings establish a structural foundation for γδ T cell-targeted immunotherapies distinct from αβ T cell strategies reliant on major-histocompatibility-complex-mediated antigen presentation.

DOI: 10.1016/j.immuni.2025.05.011

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00232-8