Dendritic cell Piezo1 stimulated by mechanical stiffness or inflammatory signals directs the differentiation of TH1 and Treg cells in cancer

  1. Yuexin Wang
  2. Hui Yang
  3. Anna Jia
  4. Yufei Wang
  5. Qiuli Yang
  6. Yingjie Dong
  7. Yueru Hou
  8. Yejin Cao
  9. Lin Dong
  10. Yujing Bi  Is a corresponding author
  11. Guangwei Liu  Is a corresponding author
  1. Beijing Normal University, China
  2. Fudan University, China
  3. Beijing Institute of Microbiology and Epidemiology, China

Abstract

Dendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the DC mechanical sensor Piezo1 stimulated by mechanical stiffness or inflammatory signals directs the reciprocal differentiation of TH1 and regulatory T (Treg) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of TH1 cells while driving the development of Treg cells in promoting cancer growth in mice. Mechanistically, Piezo1-deficient DCs regulated the secretion of the polarizing cytokines TGFβ1 and IL-12, leading to increased TGFβR2-p-Smad3 activity and decreased IL-12Rβ2-p-STAT4 activity while inducing the reciprocal differentiation of Treg and TH1 cells. In addition, Piezo1 integrated the SIRT1-hypoxia-inducible factor-1 alpha (HIF1α)-dependent metabolic pathway and calcium-calcineurin-NFAT signaling pathway to orchestrate reciprocal TH1 and Treg lineage commitment through DC-derived IL-12 and TGFβ1. Our studies provide critical insight for understanding the role of the DC-based mechanical regulation of immunopathology in directing T cell lineage commitment in tumor microenvironments.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files; Source Data files have provided for Fig.1.

Article and author information

Author details

  1. Yuexin Wang

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Hui Yang

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Anna Jia

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yufei Wang

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Qiuli Yang

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yingjie Dong

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Yueru Hou

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Yejin Cao

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Lin Dong

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Yujing Bi

    Beijing Institute of Microbiology and Epidemiology, Beijing, China
    For correspondence
    byj7801@sina.com
    Competing interests
    The authors declare that no competing interests exist.
  11. Guangwei Liu

    Beijing Normal University, Beijing, China
    For correspondence
    liugw@bnu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6008-2891

Funding

National Natural Science Foundation for Key Programm of China (31730024)

  • Guangwei Liu

National Natural Science Foundation for General Program of China (32170911)

  • Guangwei Liu

Beijing Municipal Natural Science Foundation of China (5202013)

  • Guangwei Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were approved by the Animal Ethics Committee of Fudan University, Shanghai, China, Beijing Institute of Microbiology and Epidemiology and Beijing Normal University (IACUC-DWZX-2017-003 and CLS-EAW-2017-002)

Human subjects: Normal human DCs (CC-2701; Lonza) and human cord blood CD4+ T cells (2C-200; Lonza) were obtained from Lonza Company. All human subject experiments were performed with the approval of the Ethics Committee of of Fudan University, China and Beijing Normal University, China.

Reviewing Editor

  1. Kellie N Smith, The Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: May 3, 2022
  2. Preprint posted: May 18, 2022 (view preprint)
  3. Accepted: August 20, 2022
  4. Accepted Manuscript published: August 22, 2022 (version 1)
  5. Version of Record published: September 7, 2022 (version 2)

Copyright

© 2022, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yuexin Wang
  2. Hui Yang
  3. Anna Jia
  4. Yufei Wang
  5. Qiuli Yang
  6. Yingjie Dong
  7. Yueru Hou
  8. Yejin Cao
  9. Lin Dong
  10. Yujing Bi
  11. Guangwei Liu
(2022)
Dendritic cell Piezo1 stimulated by mechanical stiffness or inflammatory signals directs the differentiation of TH1 and Treg cells in cancer
eLife 11:e79957.
https://doi.org/10.7554/eLife.79957

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