T cells in jawed vertebrates comprise two lineages, αβ T-cells and γδ T-cells, defined by the antigen receptors they express, i.e., αβ and γδ T-cell receptors (TCRs), respectively. The two lineages have different immunological roles, requiring γδ TCRs to recognize more structurally-diverse ligands¹. Nevertheless, the receptors use shared CD3 subunits to initiate signaling. Whereas the structural organization of αβ TCRs is understood^2,3, the architecture of γδ TCRs is unknown. Here, we used cryogenic electron microscopy to determine the structure of a fully-assembled, MR1-reactive human Vδ3Vγ8 TCR/CD3δγε₂ζ₂ complex bound by anti-CD3ε antibody Fab fragments^4,5. The arrangement of CD3 subunits in γδ and αβ TCRs is conserved and, although the transmembrane α-helices of the TCR-γδ and -αβ subunits differ markedly in sequence, the packing of the eight transmembrane-helix bundles is similar⁶. However, in contrast to the apparently rigid αβ TCR^2,3,6, the γδ TCR exhibits considerable conformational heterogeneity, owing to the ligand-binding TCR-γδ subunits being tethered to the CD3 subunits by their transmembrane regions only. Reducing this conformational heterogeneity by transferring the Vδ3Vγ8 TCR variable domains to an αβ TCR enhanced receptor signaling, suggesting that γδ TCR organization reflects a compromise between efficient signaling and the ability to engage structurally-diverse ligands. Our findings reveal the remarkable structural plasticity of the TCR on evolutionary timescales, and recast it as a highly versatile receptor capable of initiating signaling as either a rigid or flexible structure.

有颌脊椎动物中的T细胞包括两个谱系：αβT细胞和γδT细胞，由它们表达的抗原受体分别定义，即αβ和γδT细胞受体(TCR)。这两个谱系具有不同的免疫学作用，需要 γδ TCR 识别结构更加多样化的配体¹ 。然而，受体使用共享的 CD3 亚基来启动信号传导。虽然 αβ TCR 的结构组织已被了解^2,3 ，但 γδ TCR 的架构尚不清楚。在这里，我们使用低温电子显微镜来确定与抗 CD3ε 抗体 Fab 片段结合的完全组装的 MR1 反应性人 Vδ3Vγ8 TCR/CD3δγε ₂ ze ₂复合物的结构^4,5 。 CD3 亚基在 γδ 和 αβ TCR 中的排列是保守的，尽管 TCR-γδ 和 -αβ 亚基的跨膜 α 螺旋序列明显不同，但 8 个跨膜螺旋束的堆积是相似的⁶ 。然而，与明显刚性的 αβ TCR ^2,3,6相比，γδ TCR 表现出相当大的构象异质性，因为配体结合 TCR-γδ 亚基仅通过其跨膜区域与 CD3 亚基相连。通过将 Vδ3Vγ8 TCR 可变域转移到 αβ TCR 来减少这种构象异质性，增强了受体信号传导，表明 γδ TCR 组织反映了有效信号传导和接合结构多样化配体的能力之间的折衷。我们的研究结果揭示了 TCR 在进化时间尺度上的显着结构可塑性，并将其重新塑造为一种高度通用的受体，能够以刚性或柔性结构启动信号传导。