Single-cell RNA-seq unveils critical regulators of human FOXP3+ regulatory T cell stability

Gang Yi; Yi Zhao; Feng Xie; Fuxiang Zhu; Ziyun Wan; Jingwan Wang; Xie Wang; Kai Gao; Lixia Cao; Xinyang Li; Chen Chen; Yashu Kuang; Xiu Qiu; Huanming Yang; Jian Wang; Bing Su; Lei Chen; Wei Zhang; Yong Hou; Xun Xu; Yinyan He; Andy Tsun; Xiao Liu; Bin Li

doi:10.1016/j.scib.2020.01.002

Single-cell RNA-seq unveils critical regulators of human FOXP3⁺ regulatory T cell stability

Sci Bull (Beijing). 2020 Jul 15;65(13):1114-1124. doi: 10.1016/j.scib.2020.01.002. Epub 2020 Jan 8.

Authors

Gang Yi¹, Yi Zhao², Feng Xie³, Fuxiang Zhu³, Ziyun Wan⁴, Jingwan Wang⁴, Xie Wang⁴, Kai Gao⁴, Lixia Cao⁴, Xinyang Li⁴, Chen Chen⁵, Yashu Kuang⁶, Xiu Qiu⁶, Huanming Yang⁴, Jian Wang⁷, Bing Su³, Lei Chen³, Wei Zhang⁴, Yong Hou⁴, Xun Xu⁴, Yinyan He⁸, Andy Tsun⁹, Xiao Liu¹⁰, Bin Li¹¹

Affiliations

¹ Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Biotheus Inc., Zhuhai 519080, China.
² Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; BGI-Shenzhen, Shenzhen 518083, China; School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China.
³ Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁴ BGI-Shenzhen, Shenzhen 518083, China.
⁵ School of Mathematical Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
⁶ Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510006, China.
⁷ James D. Watson Institute of Genome Sciences, Hangzhou 310058, China.
⁸ Department of Obstetrics and Gynaecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
⁹ Biotheus Inc., Zhuhai 519080, China.
¹⁰ BGI-Shenzhen, Shenzhen 518083, China. Electronic address: liuxiao@genomics.cn.
¹¹ Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: binli@shsmu.edu.cn.

PMID: 36659163
DOI: 10.1016/j.scib.2020.01.002

Abstract

The heterogeneity and plasticity of T lymphocytes is critical for determining immune response outcomes. Functional regulatory T (Treg) cells are commonly characterized by stable FOXP3 expression and have reported to exhibit heterogeneous phenotypes under inflammatory conditions. However, the interplay between inflammation and Treg cell suppressive activity still remains elusive. Here, we utilized single-cell RNA sequencing to investigate how human Treg cells respond to the pro-inflammatory cytokine interleukin-6 (IL-6). We observed that Treg cells divided into two subpopulations after IL-6 stimulation. TIGIT^- unstable Treg cells lost FOXP3 expression and gained an effector-like T cell phenotype, whereas TIGIT⁺ Treg cells retained robust suppressive function. Single cell transcriptome analysis revealed a spectrum of cellular states of IL-6-stimulated Treg cells and how cytochrome P450 family 1 subfamily A member 1 (CYP1A1) is a crucial regulator of Treg cell suppressive capability and stability. CYP1A1-deficient human Treg cells developed a Th17-like phenotype after IL-6 stimulation. Our findings implicate CYP1A1 as a previously unidentified regulator of Treg cells that may have target potential for clinical application for biotherapies.

Keywords: Cytochrome P450 1A1; Heterogeneity; Inflammation; Interleukin-6; Treg cell; scRNA-seq.