The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes

  1. Yasmina Serroukh
  2. Chunyan Gu-Trantien
  3. Baharak Hooshiar Kashani
  4. Matthieu Defrance
  5. Thien-Phong Vu Manh
  6. Abdulkader Azouz
  7. Aurélie Detavernier
  8. Alice Hoyois
  9. Jishnu Das
  10. Martin Bizet
  11. Emeline Pollet
  12. Tressy Tabbuso
  13. Emilie Calonne
  14. Klaas van Gisbergen
  15. Marc Dalod
  16. François Fuks
  17. Stanislas Goriely
  18. Arnaud Marchant  Is a corresponding author
  1. Université Libre de Bruxelles, Belgium
  2. Aix Marseille Univ, CNRS, INSERM U1104, France
  3. Ragon Institute of MGH, MIT and Harvard, United States
  4. Sanquin Research and Landsteiner Laboratory AMC/UvA, Netherlands

Abstract

Cytotoxic CD4 (CD4CTX) T cells are emerging as an important component of anti-viral and anti-tumor immunity but the molecular basis of their development remains poorly understood. In the context of human cytomegalovirus infection, a significant proportion of CD4 T cells displays cytotoxic functions. We observed that the transcriptional program of these cells was enriched in CD8 T cell lineage genes despite the absence of ThPOK downregulation. We further show that establishment of CD4CTX-specific transcriptional and epigenetic programs occurred in a stepwise fashion along the Th1-differentiation pathway. In vitro, prolonged activation of naive CD4 T cells in presence of Th1 polarizing cytokines led to the acquisition of perforin-dependent cytotoxic activity. This process was dependent on the Th1 transcription factor Runx3 and was limited by the sustained expression of ThPOK. This work elucidates the molecular program of human CD4CTX T cells and identifies potential targets for immunotherapy against viral infections and cancer.

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The following data sets were generated

Article and author information

Author details

  1. Yasmina Serroukh

    Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  2. Chunyan Gu-Trantien

    Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  3. Baharak Hooshiar Kashani

    Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  4. Matthieu Defrance

    Laboratoire d'Epigénétique du Cancer, Université Libre de Bruxelles, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  5. Thien-Phong Vu Manh

    Centre d'Immunologie de Marseille-Luminy, Aix Marseille Univ, CNRS, INSERM U1104, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0294-342X
  6. Abdulkader Azouz

    Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  7. Aurélie Detavernier

    Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  8. Alice Hoyois

    Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  9. Jishnu Das

    Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5747-064X
  10. Martin Bizet

    Laboratoire d'Epigénétique du Cancer, Université Libre de Bruxelles, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  11. Emeline Pollet

    Centre d'Immunologie de Marseille-Luminy, Aix Marseille Univ, CNRS, INSERM U1104, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Tressy Tabbuso

    Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  13. Emilie Calonne

    Laboratoire d'Epigénétique du Cancer, Université Libre de Bruxelles, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  14. Klaas van Gisbergen

    Department of Haematopoiesis, Sanquin Research and Landsteiner Laboratory AMC/UvA, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  15. Marc Dalod

    Centre d'Immunologie de Marseille-Luminy, Aix Marseille Univ, CNRS, INSERM U1104, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  16. François Fuks

    Laboratoire d'Epigénétique du Cancer, Université Libre de Bruxelles, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  17. Stanislas Goriely

    Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7005-6195
  18. Arnaud Marchant

    Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
    For correspondence
    arnaud.marchant@ulb.ac.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0578-0467

Funding

Fonds De La Recherche Scientifique - FNRS (PhD Student Fellowship)

  • Yasmina Serroukh

Belgian Federal Public Planning Service Science Policy (Research Project Grant)

  • Stanislas Goriely
  • Arnaud Marchant

European Regional Development Fund and Walloon Region (Research Project Grant (411132-957270))

  • Stanislas Goriely
  • Arnaud Marchant

Fonds De La Recherche Scientifique - FNRS (Research Project Grant (PDR))

  • François Fuks
  • Stanislas Goriely
  • Arnaud Marchant

Fonds Erasme (PhD Student Fellowship)

  • Alice Hoyois

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

Ethics

Human subjects: Volunteers were recruited by the research centre ImmuneHealth, CHU Tivoli, La Louvière. Clinical staff informed the volunteers about the objectives of the study and obtained their written consent to use the human material for research purposes. The study and the informed consent form were approved , following approval by the Ethics committee of the CHU Tivoli, La Louvière, Belgium (Reference B09620097253). The study followed the Good Clinical Practice (ICH/GCP) guidelines, the Belgian Law and the declaration of Helsinki ("World Medical Association Declaration of Helsinki; Ethical Principles for Medical Research Involving Human Subjects").

Copyright

© 2018, Serroukh 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. Yasmina Serroukh
  2. Chunyan Gu-Trantien
  3. Baharak Hooshiar Kashani
  4. Matthieu Defrance
  5. Thien-Phong Vu Manh
  6. Abdulkader Azouz
  7. Aurélie Detavernier
  8. Alice Hoyois
  9. Jishnu Das
  10. Martin Bizet
  11. Emeline Pollet
  12. Tressy Tabbuso
  13. Emilie Calonne
  14. Klaas van Gisbergen
  15. Marc Dalod
  16. François Fuks
  17. Stanislas Goriely
  18. Arnaud Marchant
(2018)
The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes
eLife 7:e30496.
https://doi.org/10.7554/eLife.30496

Share this article

https://doi.org/10.7554/eLife.30496

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