Multiple Signaling Roles of CD3 epsilon and Its Application in CAR-T Cell Therapy

doi:10.1016/j.cell.2020.07.018

	Multiple Signaling Roles of CD3 epsilon and Its Application in CAR-T Cell Therapy
	Wu, Wei 1; Zhou, Qiuping 1; Masubuchi, Takeya 2; Shi, Xiaoshan 1,3,12,13; Li, Hua 1; Xu, Xinyi 1; Huang, Min 1; Meng, Li 1; He, Xing 1; Zhu, Hengyu 1; Gao, Shuaixin 3; Zhang, Nan 3; Jing, Ruirui 4,5,6,7; Sun, Jie 4,5,6,7; Wang, Haopeng8 ; Hui, Enfu 2; Wong, Catherine Chiulan 1,3,9,10; Xu, Chenqi 1,11
	2020-08-20
发表期刊	CELL (IF:45.5[JCR-2023],49.0[5-Year])
ISSN	0092-8674
EISSN	1097-4172
卷号	182 期号:4 页码:855-+
发表状态	已发表
DOI	10.1016/j.cell.2020.07.018
摘要	A T cell receptor (TCR) mediates antigen-induced signaling through its associated CD3 epsilon, delta, gamma, and zeta, but the contributions of different CD3 chains remain elusive. Using quantitative mass spectrometry, we simultaneously quantitated the phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of all CD3 chains upon TCR stimulation. A subpopulation of CD3 epsilon ITAMs was mono-phosphorylated, owing to Lck kinase selectivity, and specifically recruited the inhibitory Csk kinase to attenuate TCR signaling, suggesting that TCR is a self-restrained signaling machinery containing both activating and inhibitory motifs. Moreover, we found that incorporation of the CD3 epsilon cytoplasmic domain into a second-generation chimeric antigen receptor (CAR) improved antitumor activity of CAR-T cells. Mechanistically, the Csk-recruiting ITAM of CD3 epsilon reduced CAR-T cytokine production whereas the basic residue rich sequence (BRS) of CD3 epsilon promoted CAR-T persistence via p85 recruitment, Collectively, CD3 epsilon is a built-in multifunctional signal tuner, and increasing CD3 diversity represents a strategy to design next-generation CAR.
收录类别	SCI ; SCIE
语种	英语
资助项目	Chinese Academy of Sciences (CAS)[XDB29000000][QYZDB-SSW-SMC048] ; National Natural Science Foundation of China (NSFC)[31530022][31861133009][31621003] ; National Key R&D Program of China[2019YFA0111001][2018YFA0800702] ; Double First-Class University grants of China[BMU2017YJ003][BMU2018XTZ002] ; NSFC[31670919][31670751]
WOS研究方向	Biochemistry & Molecular Biology ; Cell Biology
WOS类目	Biochemistry & Molecular Biology ; Cell Biology
WOS记录号	WOS:000561488500009
出版者	CELL PRESS
WOS关键词	PROLINE-RICH SEQUENCE ; RECEPTOR ZETA ; TYROSINE PHOSPHORYLATION ; ABSOLUTE QUANTIFICATION ; MEMBRANE ASSOCIATION ; ACTIVATION MOTIFS ; SUBUNIT CONTAINS ; BINDING MOTIF ; KINASE CSK ; TCR-ZETA
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/123078
专题	生命科学与技术学院_PI研究组_王皞鹏组
通讯作者	Hui, Enfu; Wong, Catherine Chiulan; Xu, Chenqi
作者单位	1.Univ Chinese Acad Sci, Chinese Acad Sci, Ctr Excellence Mol Cell Sci, State Key Lab Mol Biol,Shanghai Inst Biochem & Ce, Shanghai 200031, Peoples R China 2.Univ Calif San Diego, Div Biol Sci, Sect Cell & Dev Biol, La Jolla, CA 92093 USA 3.Peking Univ, Hlth Sci Ctr, Hosp 1, Ctr Precis Med Multiom Res, Beijing 100191, Peoples R China 4.Zhejiang Univ, Bone Marrow Transplantat Ctr, Affiliated Hosp 1, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China 5.Zhejiang Univ, Sch Med, Dept Cell Biol, Hangzhou 310058, Zhejiang, Peoples R China 6.Zhejiang Univ, Inst Hematol, Hangzhou 310058, Zhejiang, Peoples R China 7.Lab Stem Cell & Immunotherapy Engn, Hangzhou 310058, Zhejiang, Peoples R China 8.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 9.Peking Univ, Sch Basic Med Sci, Hlth Sci Ctr, Beijing 100191, Peoples R China 10.Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China 11.Univ Chinese Acad Sci, Sch Life Sci, Hangzhou Inst Adv Study, Hangzhou 310024, Zhejiang, Peoples R China 12.Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA 13.Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA
推荐引用方式 GB/T 7714	Wu, Wei,Zhou, Qiuping,Masubuchi, Takeya,et al. Multiple Signaling Roles of CD3 epsilon and Its Application in CAR-T Cell Therapy[J]. CELL,2020,182(4):855-+.
APA	Wu, Wei.,Zhou, Qiuping.,Masubuchi, Takeya.,Shi, Xiaoshan.,Li, Hua.,...&Xu, Chenqi.(2020).Multiple Signaling Roles of CD3 epsilon and Its Application in CAR-T Cell Therapy.CELL,182(4),855-+.
MLA	Wu, Wei,et al."Multiple Signaling Roles of CD3 epsilon and Its Application in CAR-T Cell Therapy".CELL 182.4(2020):855-+.