Zinc finger protein Zfp335 controls early T cell development and survival through β-selection-dependent and -independent mechanisms

Abstract

T cell development in the thymus undergoes the process of differentiation, selective proliferation and survival from CD4-CD8- double negative (DN) stage to CD4+CD8+ double positive (DP) stage prior to the formation of CD4+ helper and CD8+ cytolytic T cells ready for circulation. Each developmental stage is tightly regulated by sequentially-operating molecular networks, of which only limited numbers of transcription regulators have been deciphered. Here we identified Zfp335 transcription factor as a new player in the regulatory network controlling thymocyte development in mice. We demonstrate that Zfp335 intrinsically controls DN to DP transition, as T cell-specific deficiency in Zfp335 leads to a substantial accumulation of DN3 along with reduction of DP, CD4+ and CD8+ thymocytes. This developmental blockade at DN stage results from the impaired intracellular TCRβ expression as well as increased susceptibility to apoptosis in thymocytes. Transcriptomic and ChIP-seq analyses revealed a direct regulation of transcription factors Bcl6 and Rorcβ by Zfp335. Importantly, enhanced expression of TCRβ and Bcl6/Rorc restores the developmental defect during DN3 to DN4 transition and improves thymocytes survival, respectively. These findings identify a critical role of Zfp335 in controlling T cell development by maintaining intracellular TCRβ expression-mediated β-selection and independently activating cell survival signaling.

Data availability

The sequencing data presented in this paper are available for download on GEO data repository with accession numbers GEO: GSE184532 and GSE184705.Source Data files have been provided for relevant figures.

The following data sets were generated

Article and author information

Author details

  1. Xin Wang

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Anjun Jiao

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Lina Sun

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Wenhua Li

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Biao Yang

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yanhong Su

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Renyi Ding

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Cangang Zhang

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Haiyan Liu

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Xiaofeng Yang

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Chenming Sun

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Baojun Zhang

    Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, China
    For correspondence
    bj.zhang@mail.xjtu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5972-1011

Funding

National Natural Science Foundation of China (3217080356)

  • Baojun Zhang

National Natural Science Foundation of China (81771673)

  • Baojun Zhang

Major International Joint Research Programme (81820108017)

  • Baojun Zhang

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 mice were housed in specific-pathogen free conditions by the Xi'an Jiaotong University Division of Laboratory Animal Research. All animal procedures were approved by the Institutional Animal Care and Use Committee of Xi'an Jiaotong University (2017-1012).

Reviewing Editor

  1. Sarah Russell, Peter MacCallum Cancer Centre, Australia

Publication history

  1. Received: November 12, 2021
  2. Preprint posted: November 21, 2021 (view preprint)
  3. Accepted: February 3, 2022
  4. Accepted Manuscript published: February 3, 2022 (version 1)
  5. Version of Record published: February 24, 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. Xin Wang
  2. Anjun Jiao
  3. Lina Sun
  4. Wenhua Li
  5. Biao Yang
  6. Yanhong Su
  7. Renyi Ding
  8. Cangang Zhang
  9. Haiyan Liu
  10. Xiaofeng Yang
  11. Chenming Sun
  12. Baojun Zhang
(2022)
Zinc finger protein Zfp335 controls early T cell development and survival through β-selection-dependent and -independent mechanisms
eLife 11:e75508.
https://doi.org/10.7554/eLife.75508
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