2. Academic Validation
  3. Transient hydroxycholesterol treatment restrains TCR signaling to promote long-term immunity

Transient hydroxycholesterol treatment restrains TCR signaling to promote long-term immunity

  • Cell Chem Biol. 2024 May 16;31(5):920-931.e6. doi: 10.1016/j.chembiol.2024.04.005.
Zhengxu Ren 1,  Kun Wang 2,  Yong Zhang 3,  Hui Chen 3,  Yiming Zhu 1,  Hua Li 1,  Jizhong Lou 4,  Haopeng Wang 5,  Chenqi Xu 6
Affiliations

Affiliations

  • 1 Key Laboratory of Multi-Cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3 Key Laboratory of Epigenetic Regulation and Intervention, Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 4 Key Laboratory of Epigenetic Regulation and Intervention, Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: jlou@ibp.ac.cn.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: wanghp@shanghaitech.edu.cn.
  • 6 Key Laboratory of Multi-Cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: cqxu@sibcb.ac.cn.
PMID: 38759618 DOI: 10.1016/j.chembiol.2024.04.005
Abstract

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.

Keywords

7-alpha-hydroxycholesterol; CD3 membrane binding; T cell receptor; TCR-T cell therapy; membrane physicochemical properties.

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