Regulatory T cells suppress the formation of potent KLRK1 and IL-7R expressing effector CD8 T cells by limiting IL-2

  1. Oksana Tsyklauri
  2. Tereza Chadimova
  3. Veronika Niederlova
  4. Jirina Kovarova
  5. Juraj Michalik
  6. Iva Malatova
  7. Sarka Janusova
  8. Olha Ivashchenko
  9. Helene Rossez
  10. Ales Drobek
  11. Hana Vecerova
  12. Virginie Galati
  13. Marek Kovar
  14. Ondrej Stepanek  Is a corresponding author
  1. Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic
  2. Institute of Microbiology of the Czech Academy of Sciences, Czech Republic
  3. University Hospital of Basel, Switzerland

Abstract

Regulatory T cells (Tregs) are indispensable for maintaining self-tolerance by suppressing conventional T cells. On the other hand, Tregs promote tumor growth by inhibiting anti-cancer immunity. In this study, we identified that Tregs increase the quorum of self-reactive CD8+ T cells required for the induction of experimental autoimmune diabetes in mice. Their major suppression mechanism is limiting available IL-2, an essential T-cell cytokine. Specifically, Tregs inhibit the formation of a previously uncharacterized subset of antigen-stimulated KLRK1+ IL7R+ (KILR) CD8+ effector T cells, which are distinct from conventional effector CD8+ T cells. KILR CD8+ T cells show a superior cell killing abilities in vivo. The administration of agonistic IL-2 immunocomplexes phenocopies the absence of Tregs, i.e., it induces KILR CD8+ T cells, promotes autoimmunity, and enhances anti-tumor responses in mice. Counterparts of KILR CD8+ T cells were found in the human blood, revealing them as a potential target for immunotherapy.

Data availability

All scRNA data analyzed in this study as well as the scripts used for the analysis are available without restrictions. The scRNAseq data generated in this study were deposited in the Gene Expression Omnibus (GSE183940).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Oksana Tsyklauri

    Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9997-5913
  2. Tereza Chadimova

    Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  3. Veronika Niederlova

    Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  4. Jirina Kovarova

    Laboratory of Tumor Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  5. Juraj Michalik

    Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  6. Iva Malatova

    Laboratory of Tumor Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  7. Sarka Janusova

    Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0111-497X
  8. Olha Ivashchenko

    Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  9. Helene Rossez

    Department of Biomedicine, University Hospital of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  10. Ales Drobek

    Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  11. Hana Vecerova

    Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  12. Virginie Galati

    Department of Biomedicine, University Hospital of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  13. Marek Kovar

    Laboratory of Tumor Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6602-1678
  14. Ondrej Stepanek

    Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
    For correspondence
    ondrej.stepanek@img.cas.cz
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2735-3311

Funding

European Research Council (FunDiT)

  • Ondrej Stepanek

European Union - Next Generation EU (LX22NPO5103)

  • Ondrej Stepanek

European Union - Next Generation EU (LX22NPO5102)

  • Marek Kovar

Czech Science Foundation (19-03435Y)

  • Ondrej Stepanek

Czech Science Foundation (22-20548S)

  • Marek Kovar

Research Fund for Young Scientists at the University of Basel (DMS2336)

  • Ondrej Stepanek

Charles University Grant Agency (1706119)

  • Oksana Tsyklauri

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

Reviewing Editor

  1. Juan Carlos Zúñiga-Pflücker, University of Toronto, Sunnybrook Research Institute, Canada

Ethics

Animal experimentation: Animal protocols were performed in accordance with the laws of the Czech Republic and Cantonal and Federal laws of Switzerland, and approved by the Czech Academy of Sciences (identification no. 11/2016, 81/2018, 15/2019) or the Cantonal Veterinary Office of Baselstadt, Switzerland, respectively.

Version history

  1. Preprint posted: November 12, 2021 (view preprint)
  2. Received: April 7, 2022
  3. Accepted: January 27, 2023
  4. Accepted Manuscript published: January 27, 2023 (version 1)
  5. Version of Record published: February 28, 2023 (version 2)

Copyright

© 2023, Tsyklauri 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. Oksana Tsyklauri
  2. Tereza Chadimova
  3. Veronika Niederlova
  4. Jirina Kovarova
  5. Juraj Michalik
  6. Iva Malatova
  7. Sarka Janusova
  8. Olha Ivashchenko
  9. Helene Rossez
  10. Ales Drobek
  11. Hana Vecerova
  12. Virginie Galati
  13. Marek Kovar
  14. Ondrej Stepanek
(2023)
Regulatory T cells suppress the formation of potent KLRK1 and IL-7R expressing effector CD8 T cells by limiting IL-2
eLife 12:e79342.
https://doi.org/10.7554/eLife.79342

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https://doi.org/10.7554/eLife.79342

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    LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).

    Clinical trial number:

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