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Recirculating IL-1R2+ Tregs fine-tune intrathymic Treg development under inflammatory conditions

Cellular & Molecular Immunology volume 18, pages 182–193 (2021)Cite this article

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Abstract

The vast majority of Foxp3+ regulatory T cells (Tregs) are generated in the thymus, and several factors, such as cytokines and unique thymic antigen-presenting cells, are known to contribute to the development of these thymus-derived Tregs (tTregs). Here, we report the existence of a specific subset of Foxp3+ Tregs within the thymus that is characterized by the expression of IL-1R2, which is a decoy receptor for the inflammatory cytokine IL-1. Detailed flow cytometric analysis of the thymocytes from Foxp3hCD2xRAG1GFP reporter mice revealed that the IL-1R2+ Tregs are mainly RAG1GFP– and CCR6+CCR7–, demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and that they have an activated phenotype. In the spleen, the majority of IL-1R2+ Tregs express neuropilin-1 (Nrp-1) and Helios, suggesting a thymic origin for these Tregs. Interestingly, among all tissues studied, the highest frequency of IL-1R2+ Tregs was observed in the thymus, indicating preferential recruitment of this Treg subset by the thymus. Using fetal thymic organ cultures (FTOCs), we demonstrated that increased concentrations of exogenous IL-1β blocked intrathymic Treg development, resulting in a decreased frequency of CD25+Foxp3+ tTregs and an accumulation of CD25+Foxp3− Treg precursors. Interestingly, the addition of IL-1R2+ Tregs, but not IL-1R2− Tregs, to reaggregated thymic organ cultures (RTOCs) abrogated the IL-1β-mediated blockade, demonstrating that these recirculating IL-1R2+ Tregs can quench IL-1 signaling in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.

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Fig. 1: Phenotyping IL-1R2+Foxp3+ Tregs in the thymus.
Fig. 2: Phenotyping IL-1R2+Foxp3+ Tregs in the spleen.
Fig. 3: Expression level of IL-1R2 on tissue-resident Tregs.
Fig. 4: Expression of IL-1R1 and its ligands, IL-1α and IL-1β, in the thymus.
Fig. 5: Exogenous IL-1β affects tTreg development in the FTOCs.
Fig. 6: Normal tTreg generation despite increased intrathymic IL-1β levels after CFA treatment.
Fig. 7: IL-1R2+Foxp3+ Tregs fine-tune tTreg development in the RTOCs under inflammatory conditions.

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Acknowledgements

We thank Marina Wuttke and Lothar Groebe for their technical and cell sorting support. This work was supported by the CRC 738 (to J.H.), CRC/TR 128 (to A.W.) and CRC/TRR 221 (to M.F.) of the German Research Foundation and by grants from the European Research Council (ERC-CoG, #648145 REGiREG) to M.F. Y.E. was supported by Ph.D scholarship program no. 57129429 of the German Academic Exchange Service (DAAD).

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  1. These authors contributed equally: Eirini Nikolouli, Yassin Elfaki

Authors and Affiliations

  1. Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany

    Eirini Nikolouli, Yassin Elfaki, Susanne Herppich & Jochen Huehn

  2. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg—University Mainz, Mainz, Germany

    Carsten Schelmbauer, Ilgiz A. Mufazalov & Ari Waisman

  3. Regensburg Center for Interventional Immunology (RCI), Chair for Immunology, University Regensburg and University Hospital Regensburg, Regensburg, Germany

    Michael Delacher & Markus Feuerer

  4. Institute of Transplant Immunology, Integrated Research and Treatment Center Transplantation, IFB-Tx, Hannover Medical School, Hannover, Germany

    Christine Falk

  5. Hannover Medical School, Hannover, Germany

    Jochen Huehn

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Contributions

E.N., Y.E., S.H., M.D., C.S. and I.A.M. performed the experiments and interpreted the data. A.W., C.F. and M.F. interpreted the data. E.N. and J.H. designed the research, interpreted the data, and wrote the paper.

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Correspondence to Jochen Huehn.

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Nikolouli, E., Elfaki, Y., Herppich, S. et al. Recirculating IL-1R2+ Tregs fine-tune intrathymic Treg development under inflammatory conditions. Cell Mol Immunol 18, 182–193 (2021). https://doi.org/10.1038/s41423-019-0352-8

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Keywords

  • Thymus
  • Treg development
  • Inflammation
  • IL-1 system

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