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.
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.
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
Further reading
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Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RA−CCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3−CCR7+Helios−CD127−CD8+) and pro-inflam Macs (CD206−CD163−CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163−CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206− pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.
