由 pMHC 连接的完全组装的肿瘤特异性 T 细胞受体的结构

SCI

4 September 2022

Structure of a fully assembled tumor-specific T cell receptor ligated by pMHC

（Cell；IF:66.85）

Sušac L, Vuong MT, Thomas C, et al. Structure of a fully assembled tumor-specific T cell receptor ligated by pMHC. Cell. 2022

CORRESPONDENCE TO : tampe@em.uni-frankfurt.de; simon.davis@imm.ox.ac.uk

Abstract | 

The T cell receptor (TCR) expressed by T lymphocytes initiates protective immune responses to pathogens and tumors. To explore the structural basis of how TCR signaling is initiated when the receptor binds to peptide-loaded major histocompatibility complex (pMHC) molecules, we used cryogenic electron microscopy to determine the structure of a tumor-reactive TCRαβ/CD3δγε2ζ2 complex bound to a melanoma-specific human class I pMHC at 3.08 Å resolution. The antigen-bound complex comprises 11 subunits stabilized by multivalent interactions across three structural layers, with clustered membrane-proximal cystines stabilizing the CD3-εδ and CD3-εγ heterodimers. Extra density sandwiched between transmembrane helices reveals the involvement of sterol lipids in TCR assembly. The geometry of the pMHC/TCR complex suggests that efficient TCR scanning of pMHC requires accurate pre-positioning of T cell and antigen-presenting cell membranes. Comparisons of the ligand-bound and unliganded receptors, along with molecular dynamics simulations, indicate that TCRs can be triggered in the absence of spontaneous structural rearrangements.

T 淋巴细胞表达的 T 细胞受体 (TCR) 能够启动对病原体和肿瘤的保护性免疫反应。为了探索当受体与载肽的主要组织相容性复合物 (pMHC) 分子结合时如何启动 TCR 信号传导的结构基础，我们使用低温电子显微镜在3.08 A˚的分辨率下来确定与黑色素瘤人类特异性I类pMHC结合的肿瘤反应性 TCRab/CD3dgε 2z2 复合物的结构。抗原结合复合物包含 11 个亚基，通过跨三个结构层的多价相互作用稳定，其中成簇的膜近端胱氨酸稳定 CD3-ε d 和 CD3-ε g 异二聚体。夹在跨膜螺旋之间的额外密度揭示了甾醇脂质参与 TCR 组装。pMHC/TCR 复合物的几何形状表明，pMHC 的有效 TCR 扫描需要 T 细胞和抗原呈递细胞膜的准确预定位。配体结合和未配体受体之间的比较，以及分子动力学模拟，表明 TCR 可以在没有自发结构重排的情况下被触发。