Hoque Mohammed, Grigg John Benji, Ramlall Trudy, Jones Jennifer, McGoldrick Luke L, Lin John C, Olson William C, Smith Eric, Franklin Matthew C, Zhang Tong, Saotome Kei
Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA.
Nat Commun. 2025 Jan 2;16(1):318. doi: 10.1038/s41467-024-55467-5.
The T-cell receptor (TCR)/CD3 complex plays an essential role in the immune response and is a key player in cancer immunotherapies. There are two classes of TCR/CD3 complexes, defined by their TCR chain usage (αβ or γδ). Recently reported structures have revealed the organization of the αβ TCR/CD3 complex, but similar studies regarding the γδ TCR/CD3 complex have lagged behind. Here, we report cryoelectron microscopy (cryoEM) structural analysis of two γδ TCRs, G115 (Vγ9 Vδ2) and 9C2 (Vγ5 Vδ1), in complex with CD3 subunits. Our results show that the overall subunit organization of the γδ TCR/CD3 complexes is similar to αβ TCRs. However, both γδ TCRs display highly mobile extracellular domains (ECDs), unlike αβ TCRs, which have TCR ECDs that are rigidly coupled to its transmembrane (TM) domains. We corroborate this finding in cells by demonstrating that a γδ T-cell specific antibody can bind a site that would be inaccessible in the more rigid αβ TCR/CD3 complex. Furthermore, we observed that the Vγ5 Vδ1 complex forms a TCR γ5 chain-mediated dimeric species whereby two TCR/CD3 complexes are assembled. Collectively, these data shed light on γδ TCR/CD3 complex formation and may aid the design of γδ TCR-based therapies.
T细胞受体（TCR）/CD3复合物在免疫反应中起关键作用，是癌症免疫治疗中的关键参与者。TCR/CD3复合物有两类，根据其TCR链的使用情况（αβ或γδ）来定义。最近报道的结构揭示了αβ TCR/CD3复合物的组成，但关于γδ TCR/CD3复合物的类似研究却滞后了。在此，我们报告了与CD3亚基形成复合物的两种γδ TCR（G115，Vγ9 Vδ2和9C2，Vγ5 Vδ1）的冷冻电镜（cryoEM）结构分析。我们的结果表明，γδ TCR/CD3复合物的整体亚基组成与αβ TCR相似。然而，与αβ TCR不同，两种γδ TCR均显示出高度可移动的细胞外结构域（ECD），αβ TCR的TCR ECD与其跨膜（TM）结构域紧密相连。我们通过证明一种γδ T细胞特异性抗体可以结合在更刚性的αβ TCR/CD3复合物中无法接近的位点，在细胞中证实了这一发现。此外，我们观察到Vγ5 Vδ1复合物形成了一种由TCR γ5链介导的二聚体，其中组装了两个TCR/CD3复合物。这些数据共同揭示了γδ TCR/CD3复合物的形成，可能有助于基于γδ TCR的疗法的设计。
