西湖大学周强等研究人员合作揭示人类γδ T细胞受体-CD3复合物的结构。该项研究成果于2024年4月24日在线发表在《自然》杂志上。

研究人员表示，γδ T 细胞是一种独特的T细胞亚群，在各种免疫反应和免疫病理中至关重要。γδT细胞产生的γδT细胞受体（TCR）能识别多种抗原，而不依赖于主要组织相容性复合体。γδ TCR与CD3亚基结合，启动T细胞活化，在免疫疗法中具有巨大潜力。

研究人员报告了两种典型的人类Vγ9Vδ2和Vγ5Vδ1 TCR-CD3 复合物的结构，揭示了取决于Vγ使用情况的两种不同的组装机制。Vγ9Vδ2 TCR-CD3 复合物是单体，TCRγ/TCRδ胞外域（ECD）和连接肽（CP）具有相当大的构象灵活性。CP的长度可调节配体结合和T细胞活化。

此外，一种胆固醇样分子楔入跨膜区，在TCR信号传导中发挥抑制作用。Vγ5Vδ1 TCR-CD3复合物显示出一种二聚体结构，其中两个原体通过其TCR ECD的Vγ5结构域背靠背嵌套。生化和生物物理实验进一步证实了这种二聚体结构。重要的是，Vγ5Vδ1 TCR的二聚体形式对T细胞的活化至关重要。这些发现揭示了γδ TCR-CD3复合物的组织原理，为了解γδ TCR的独特性质提供了见解，有助于免疫治疗干预。

附：英文原文

Title: Structures of human γδ T cell receptor–CD3 complex

Author: Xin, Weizhi, Huang, Bangdong, Chi, Ximin, Liu, Yuehua, Xu, Mengjiao, Zhang, Yuanyuan, Li, Xu, Su, Qiang, Zhou, Qiang

Issue&Volume: 2024-04-24

Abstract: Gamma delta (γδ) T cells, a unique T cell subgroup, are crucial in various immune responses and immunopathology1-3. The γδ T cell receptor (TCR), generated by γδ T cells, recognizes a diverse range of antigens independently of the major histocompatibility complex2. The γδ TCR associates with CD3 subunits, initiating T cell activation and holding great potential in immunotherapy4. Here, we report the structures of two prototypical human Vγ9Vδ2 and Vγ5Vδ1 TCR–CD3 complexes5,6, unveiling two distinct assembly mechanisms that depend on Vγ usage. The Vγ9Vδ2 TCR–CD3 complex is monomeric, with considerable conformational flexibility in the TCRγ/TCRδ extracellular domain (ECD) and connecting peptides (CPs). The length of CPs regulates the ligand association and T cell activation. Additionally, a cholesterol-like molecule wedges into the transmembrane region, exerting an inhibitory role in TCR signaling. The Vγ5Vδ1 TCR–CD3 complex displays a dimeric architecture, where two protomers nestle back-to-back via their Vγ5 domains of TCR ECDs. Our biochemical and biophysical assays further corroborate the dimeric structure. Importantly, the dimeric form of the Vγ5Vδ1 TCR is essential for T cell activation. These findings reveal organizing principles of the γδ TCR–CD3 complex, providing insights into the γδ TCR unique properties and facilitating immunotherapeutic interventions.

DOI: 10.1038/s41586-024-07439-4

Source: https://www.nature.com/articles/s41586-024-07439-4