Regulatory T cells suppress the formation of potent KLRK1 and IL-7R expressing effector CD8 T cells by limiting IL-2
- Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic
- Institute of Microbiology of the Czech Academy of Sciences, Czech Republic
- 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).
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Regulatory T cells suppress the formation of super-effector CD8 T cells by limiting IL-2NCBI Gene Expression Omnibus, GSE183940.
Article and author information
Author details
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
- 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
- Preprint posted: November 12, 2021 (view preprint)
- Received: April 7, 2022
- Accepted: January 27, 2023
- Accepted Manuscript published: January 27, 2023 (version 1)
- 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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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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