小柯机器人

德国阿尔伯特-路德维希-弗赖堡大学Susana Minguet研究组近日取得一项新成果。他们发现Lck与CD3ε的非典型结合促进T细胞抗原受体（TCR）信号传导和CAR功能。该研究于2020年7月20日发表于《自然-免疫学》。

研究人员揭示了之前未知的CD3ε细胞质尾巴结合形式，其与Lck SH3结构域以非典型的方式相互作用，SH3是受体激酶（RK）基序。RK基序只有与TCR相接时才会暴露出来，这揭示了配体结合是如何招募Lck的。Lck SH3结构域与暴露的RK基序结合引起Lck活化、CD3磷酸化、T细胞活化和局部胸腺细胞发育增强。

将RK基序引入基于41BB的嵌合抗原受体可以增强其在体内和体外的抗肿瘤功能。该发现帮助人类更好地理解TCR的功能，这可能会促进对嵌合抗原受体设计的合理改善，以治疗癌症。

据悉，TCR信号的开启需要酪氨酸激酶Lck对CD3细胞质尾巴进行磷酸化。尚不清楚Lck如何被招募到TCR以开启信号传导。

附：英文原文

Title: Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function

Author: Frederike A. Hartl, Esmeralda Beck-Garca, Nadine M. Woessner, Lea J. Flachsmann, Rub M.-H. Velasco Crdenas, Simon M. Brandl, Sanaz Taromi, Gina J. Fiala, Anna Morath, Pankaj Mishra, O. Sascha Yousefi, Julia Zimmermann, Nico Hoefflin, Maja Khn, Birgitta M. Whrl, Robert Zeiser, Kristian Schweimer, Stefan Gnther, Wolfgang W. Schamel, Susana Minguet

Issue&Volume: 2020-07-20

Abstract: Initiation of T cell antigen receptor (TCR) signaling involves phosphorylation of CD3 cytoplasmic tails by the tyrosine kinase Lck. How Lck is recruited to the TCR to initiate signaling is not well known. We report a previously unknown binding motif in the CD3ε cytoplasmic tail that interacts in a noncanonical mode with the Lck SH3 domain: the receptor kinase (RK) motif. The RK motif is accessible only upon TCR ligation, demonstrating how ligand binding leads to Lck recruitment. Binding of the Lck SH3 domain to the exposed RK motif resulted in local augmentation of Lck activity, CD3 phosphorylation, T cell activation and thymocyte development. Introducing the RK motif into a well-characterized 41BB-based chimeric antigen receptor enhanced its antitumor function in vitro and in vivo. Our findings underscore how a better understanding of the functioning of the TCR might promote rational improvement of chimeric antigen receptor design for the treatment of cancer.

DOI: 10.1038/s41590-020-0732-3

Source: https://www.nature.com/articles/s41590-020-0732-3

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