T细胞受体
期限(时间)
瞬态(计算机编程)
免疫
细胞生物学
神经科学
生物
免疫学
免疫系统
计算机科学
T细胞
物理
量子力学
操作系统
作者
Zhengxu Ren,Kun Wang,Yong Zhang,H. Chen,Yiming Zhu,Hua Li,Jizhong Lou,Haopeng Wang,Chenqi Xu
标识
DOI:10.1016/j.chembiol.2024.04.005
摘要
T cell receptor (TCR) plays a fundamental role in adaptive immunity, and TCR-T cell therapy holds great promise for treating solid tumors and other diseases. However, there is a noticeable absence of chemical tools tuning TCR activity. In our study, we screened natural sterols for their regulatory effects on T cell function and identified 7-alpha-hydroxycholesterol (7a-HC) as a potent inhibitor of TCR signaling. Mechanistically, 7a-HC promoted membrane binding of CD3ε cytoplasmic domain, a crucial signaling component of the TCR-CD3 complex, through alterations in membrane physicochemical properties. Enhanced CD3ε membrane binding impeded the condensation between CD3ε and the key kinase Lck, thereby inhibiting Lck-mediated TCR phosphorylation. Transient treatments of TCR-T cells with 7a-HC resulted in reduced signaling strength, increased memory cell populations, and superior long-term antitumor functions. This study unveils a chemical regulation of TCR signaling, which can be exploited to enhance the long-term efficacy of TCR-T cell therapy.
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