Structures of human γδ T cell receptor-CD3 complex

• 成果类型: Article
• 署名作者: Xin, Weizhi; Huang, Bangdong; Chi, Ximin; Liu, Yuehua; Xu, Mengjiao; Zhang, Yuanyuan; Li, Xu; Su, Qiang; Zhou, Qiang
• 署名单位: Westlake University; Westlake Laboratory; Westlake University; Xiamen University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6612
• DOI: 10.1038/s41586-024-07439-4
• 发表日期: 2024-06-06
• 关键词: cryo-em structure; antigen; tcr; RECOGNITION; expression; protein; validation; inhibition; molecules; regions

摘要

Gamma delta (gamma delta) T cells, a unique T cell subgroup, are crucial in various immune responses and immunopathology 1-3 . The gamma delta T cell receptor (TCR), which is generated by gamma delta T cells, recognizes a diverse range of antigens independently of the major histocompatibility complex 2 . The gamma delta TCR associates with CD3 subunits, initiating T cell activation and holding great potential in immunotherapy 4 . Here we report the structures of two prototypical human V gamma 9V delta 2 and V gamma 5V delta 1 TCR-CD3 complexes 5,6 , revealing two distinct assembly mechanisms that depend on V gamma usage. The V gamma 9V delta 2 TCR-CD3 complex is monomeric, with considerable conformational flexibility in the TCR gamma-TCR delta extracellular domain and connecting peptides. The length of the connecting peptides regulates the ligand association and T cell activation. A cholesterol-like molecule wedges into the transmembrane region, exerting an inhibitory role in TCR signalling. The V gamma 5V delta 1 TCR-CD3 complex displays a dimeric architecture, whereby two protomers nestle back to back through the V gamma 5 domains of the TCR extracellular domains. Our biochemical and biophysical assays further corroborate the dimeric structure. Importantly, the dimeric form of the V gamma 5V delta 1 TCR is essential for T cell activation. These findings reveal organizing principles of the gamma delta TCR-CD3 complex, providing insights into the unique properties of gamma delta TCR and facilitating immunotherapeutic interventions. The assembly of the gamma delta TCR depends on V gamma usage.