Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy.

Cell 2020 Aug 20

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A T cell receptor (TCR) mediates antigen-induced signaling through its associated CD3ε, δ, γ, and ζ, 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 CD3ε 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 CD3ε cytoplasmic domain into a second-generation chimeric antigen receptor (CAR) improved antitumor activity of CAR-T cells. Mechanistically, the Csk-recruiting ITAM of CD3ε reduced CAR-T cytokine production whereas the basic residue rich sequence (BRS) of CD3ε promoted CAR-T persistence via p85 recruitment. Collectively, CD3ε is a built-in multifunctional signal tuner, and increasing CD3 diversity represents a strategy to design next-generation CAR. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Wei Wu, Qiuping Zhou, Takeya Masubuchi, Xiaoshan Shi, Hua Li, Xinyi Xu, Min Huang, Li Meng, Xing He, Hengyu Zhu, Shuaixin Gao, Nan Zhang, Ruirui Jing, Jie Sun, Haopeng Wang, Enfu Hui, Catherine Chiulan Wong, Chenqi Xu. Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy. Cell. 2020 Aug 20;182(4):855-871.e23