Zhu Yuwei, Gao Wenbo, Zheng Jianlin, Bai Ye, Tian Xinyu, Huang Tengjin, Lu Zebin, Dong De, Zhang Anqi, Guo Changyou, Huang Zhiwei
HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China.
HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China; Westlake Center for Genome Editing, Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; New Cornerstone Science Institute, Harbin Institute of Technology, Harbin 150080, China.
Immunity. 2025 Apr 30. doi: 10.1016/j.immuni.2025.04.012.
Phosphoantigens (pAgs), produced by infected or cancer cells, trigger the assembly of a membrane receptor complex comprising butyrophilin (BTN) members BTN3A1 and BTN2A1, leading to the activation of γδ T cells. BTN3A2 or BTN3A3 forms heteromers with BTN3A1, exhibiting higher γδ T cell receptor (TCR)-stimulating activity than BTN3A1 homomers. Cryoelectron microscopy (cryo-EM) structure reveals a pAg-induced BTN2A1-BTN3A1 heterotetramer with a 2:2 stoichiometry, stabilized by interactions between the intracellular B30.2 domains and the extracellular immunoglobulin V (IgV) domains. BTN3A2 or BTN3A3 heterodimerizes with BTN3A1, forming a pAg-induced tetrameric complex with BTN2A1. However, BTN3A1 heterodimers are more stable than BTN3A1 homodimers in this interaction. Cryo-EM reveals that BTN2A1-BTN3A1-BTN3A2 binds two γδ TCR ectodomains, with one being sandwiched between the IgV domains of BTN2A1 and BTN3A2, while the other interacts with the free BTN2A1 IgV in the complex, as evidenced by functional data. Together, our findings uncover the mechanism of ligand-induced inside-out stabilization of BTN receptor complexes for dimeric activation of γδ TCR.
由受感染细胞或癌细胞产生的磷酸抗原（pAgs）会触发一种膜受体复合物的组装，该复合物包含嗜乳脂蛋白（BTN）成员BTN3A1和BTN2A1，从而导致γδ T细胞的激活。BTN3A2或BTN3A3与BTN3A1形成异源二聚体，表现出比BTN3A1同源二聚体更高的γδ T细胞受体（TCR）刺激活性。冷冻电子显微镜（cryo-EM）结构揭示了一种由pAg诱导的BTN2A1-BTN3A1异源四聚体，其化学计量比为2:2，通过细胞内B30.2结构域与细胞外免疫球蛋白V（IgV）结构域之间的相互作用而稳定。BTN3A2或BTN3A3与BTN3A1异源二聚化，与BTN2A1形成一种由pAg诱导的四聚体复合物。然而，在这种相互作用中，BTN3A1异源二聚体比BTN3A1同源二聚体更稳定。冷冻电子显微镜显示，BTN2A1-BTN3A1-BTN3A2结合两个γδ TCR胞外结构域，其中一个夹在BTN2A1和BTN3A2的IgV结构域之间，而另一个与复合物中游离的BTN2A1 IgV相互作用，功能数据证明了这一点。总之，我们的研究结果揭示了配体诱导的BTN受体复合物由内向外稳定以实现γδ TCR二聚体激活的机制。
