英国牛津大学Simon J. Davis、德国法兰克福大学Robert Tampé等研究人员合作解析出由pMHC连接的一个完全组装的肿瘤特异性T细胞受体结构。相关论文于2022年8月18日发表在《细胞》杂志上。

为了探索当T细胞受体（TCR）结合到含有肽的主要组织相容性复合物（pMHC）分子时，TCR信号是如何启动的结构基础，研究人员使用冷冻电镜以3.08埃的分辨率确定了与黑色素瘤特异性人类I类pMHC结合的肿瘤反应性TCRαβ/CD3δγε2ζ2复合物的结构。与抗原结合的复合物由11个亚单位组成，通过三个结构层的多价相互作用而稳定，膜近端有成群的胱氨酸稳定CD3-εδ和CD3-εγ异构体。夹在跨膜螺旋之间的额外密度揭示了甾醇脂类参与TCR的组装。

pMHC/TCR复合物的几何形状表明，TCR对pMHC的有效扫描需要T细胞和抗原呈递细胞膜的准确预定位。对配体结合的受体和未配体的受体的比较，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。

据悉，由T淋巴细胞表达的TCR启动了对病原体和肿瘤的保护性免疫反应。

附：英文原文

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

Author: Lukas Suac, Mai T. Vuong, Christoph Thomas, Sren von Bülow, Caitlin O’Brien-Ball, Ana Mafalda Santos, Ricardo A. Fernandes, Gerhard Hummer, Robert Tampé, Simon J. Davis

Issue&Volume: 2022/08/18

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 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.

DOI: 10.1016/j.cell.2022.07.010

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00913-8