1. Academic Validation
  2. IL-4 inhibits regulatory T cells differentiation by HDAC9-mediated epigenetic regulation

IL-4 inhibits regulatory T cells differentiation by HDAC9-mediated epigenetic regulation

  • Cell Death Dis. 2021 May 18;12(6):501. doi: 10.1038/s41419-021-03769-7.
Jikai Cui  # 1 Heng Xu  # 1 Jizhang Yu  # 1 Yuan Li 1 Zhang Chen 1 Yanqiang Zou 1 Xi Zhang 1 Yifan Du 1 Jiahong Xia 2 Jie Wu 3
Affiliations

Affiliations

  • 1 Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 2 Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. jiahong.xia@hust.edu.cn.
  • 3 Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. wujie426@hust.edu.cn.
  • # Contributed equally.
Abstract

Regulatory T cells play a crucial role in orchestrating immune response and maintaining immune tolerance, and the expression of the Foxp3 gene is indispensable to the differentiation of regulatory T cells. IL-4 shows strong inhibitory effects on Foxp3 expression and regulatory T cells differentiation, but the detailed mechanisms are still unclear. Here, we revealed that epigenetic modulations are key to this process. Specifically, the inhibition was found to be STAT6 dependent, and HDAC9 was involved with the process of histone deacetylation at the Foxp3 locus, subsequently decreasing chromatin accessibility and Foxp3 gene transcription. Pan-histone deacetylation inhibitors, especially sodium butyrate, notably abolished the inhibitory effects of IL-4 and ameliorated allergic airway inflammation in mouse models. Our research provides important mechanistic insights into how IL-4 inhibits regulatory T cells differentiation and suggests the therapeutic potential of the sodium butyrate in allergic airway disease.

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