美国达纳-法伯癌症研究所Ellis L. Reinherz和Jia-huai Wang研究组合作取得最新进展。他们发现在胸腺细胞β-选择过程中，pre-T细胞受体（preTCRs）以拓扑结构方式采样自身配体。这一研究成果发表在2020年12月17日的《科学》杂志上。

使用X射线晶体学，他们显示了preTCR如何将其单个可变域（Vβ）的凹面β-折叠表面“水平”地抓住凸出的MHCα2-螺旋。相比之下，αβTCR的目的是使其配对的VαVβ模块的所有六个互补决定区（CDR）环识别“垂直”头对头结合中与MHC分子（pMHCs）结合的肽。preTCR的拓扑拟合可确保CDR3β到达肽的特征性C末端片段以进行pMHC采样，从而建立随后的αβTCR典型对接模型。

“水平”对接排除了种系CDR1β–和CDR2β–MHC的结合，从而在αβTCR介导的选择优化之前拓宽了β链库的多样性。因此，一个亚基相继调节相关多组分受体的识别逻辑。

据悉，自我歧视是在胸腺细胞发育过程中编程的一个关键但不确定的分子过程，它需要大量的preTCRs和αβTCR。

附：英文原文

Title: Pre–T cell receptors topologically sample self-ligands during thymocyte β-selection

Author: Xiaolong Li, Réka Mizsei, Kemin Tan, Robert J. Mallis, Jonathan S. Duke-Cohan, Aoi Akitsu, Paul W. Tetteh, Abhinav Dubey, Wonmuk Hwang, Gerhard Wagner, Matthew J. Lang, Haribabu Arthanari, Jia-huai Wang, Ellis L. Reinherz

Issue&Volume: 2020/12/17

Abstract: Self-discrimination, a critical but ill-defined molecular process programmed during thymocyte development, requires myriad pre-T cell receptors (preTCRs) and αβTCRs. Using X-ray crystallography, we show how a preTCR applies the concave β-sheet surface of its single variable domain (Vβ) to “horizontally” grab the protruding MHC α2-helix. By contrast, αβTCRs purpose all six complementary-determining region (CDR) loops of their paired VαVβ module to recognize peptides bound to MHC molecules (pMHCs) in “vertical” head-to-head binding. The preTCR topological fit ensures that CDR3β reaches the peptide’s featured C-terminal segment for pMHC sampling, establishing the subsequent αβTCR canonical docking mode. “Horizontal” docking precludes germline CDR1β– and CDR2β–MHC binding to broaden β-chain repertoire diversification before αβTCR-mediated selection refinement. Thus, one subunit successively attunes the recognition logic of related multicomponent receptors.

DOI: 10.1126/science.abe0918

Source: https://science.sciencemag.org/content/early/2020/12/16/science.abe0918