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Recirculating IL-1R2 Tregs fine-tune intrathymic Treg development under inflammatory conditions.
Nikolouli, Eirini Elfaki, Yassin Herppich, Susanne Schelmbauer, Carsten Delacher, Michael Falk, Christine Mufazalov, Ilgiz A Waisman, Ari Feuerer, Markus
Nikolouli, Eirini
Elfaki, Yassin
Herppich, Susanne
Schelmbauer, Carsten
Delacher, Michael
Falk, Christine
Mufazalov, Ilgiz A
Waisman, Ari
Feuerer, Markus
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2020-01-27
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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.
Citation
Cell Mol Immunol. 2020 Jan 27. pii: 10.1038/s41423-019-0352-8. doi: 10.1038/s41423-019-0352-8.
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Article
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en
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2042-0226