Human regulatory T-cell development is dictated by Interleukin-2 and -15 expressed in a non-overlapping pattern in the thymus
Abstract
Thymus-derived FOXP3-expressing regulatory T-cells (tTregs) are master orchestrators of physiological and pathological immune responses, thus constituting ideal targets for the treatment of autoimmunity. Despite their clinical importance, the developmental program governing their differentiation in the human thymus remains poorly understood. Here, we investigated the role of common gamma-chain cytokines in human tTreg differentiation, by performing gain- and loss-of-function experiments in 3D and 2D postnatal thymic cultures. We identified IL-2 and IL-15 as key molecular determinants in this process and excluded a major function for IL-4, IL-7 and IL-21. Mechanistically, IL-2 and IL-15 were equally able to drive tTreg precursor differentiation into FOXP3(+) cells, and promote tTreg proliferation and survival. Both cytokines also increased the expression levels of molecules associated with effector function within FOXP3(+) subsets, supporting their involvement in tTreg functional maturation. Furthermore, we revealed that IL-2 and IL-15 are expressed in a non-overlapping pattern in the human thymus, with the former produced mainly by mature αβ and γδ thymocytes and the latter by monocyte/macrophages and B lymphocytes. Our results identify core mechanisms dictating human tTreg development, with IL-2 and IL-15 defining specific niches required for tTreg lineage stabilization and differentiation, with implications for their therapeutic targeting in autoimmune conditions.
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CD25 expression precedes FOXP3 expression during Treg development in the thymus.
“Given that CD25 expression precedes FOXP3 expression during Treg development in the thymus [405]”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [405]
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Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)
Cossarizza, A., Chang, H., Radbruch, A., Abrignani, S., Addo, R., Akdis, M., Andrä, I., Andreata, F., Annunziato, F., Arranz, E., et al. (2021) · European Journal of Immunology · doi:10.1002/eji.202170126 · Cited by 531 · see citing works
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- Authors
- Caramalho, I., Nunes-Silva, V., Pires, A. R., Mota, C., Pinto, A. I., Nunes-Cabaço, H., Foxall, R. B., & Sousa, A. E.
- Affiliations
- University of Lisbon (PT)
- Venue
- Journal of Autoimmunity
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 56
- Pages
- 98-110
- ISSN
- 0896-8411 (ISSN-L)
- OpenAlex
- W2088490984
- Cited by
- 42
- References
- 55
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 1 · 2019: 3 · 2018: 6 · 2017: 3 · 2016: 3 · 2015: 2 · 2013: 1
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Autoimmunity (publishedVersion)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion)
- Funders
- Fundação para a Ciência e a Tecnologia (PTDC/SAU-IMU/113541/2009)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- regulatory T cells, thymic Treg development, Foxp3, interleukin-2, IL-15, common gamma chain cytokines, thymic microenvironment, thymocytes, monocytes/macrophages, B cells, autoimmunity
- MeSH terms
- Cell Differentiation, Cell Survival, Humans, Interleukin-2, Lymphocyte Activation, Phenotype, Thymus Gland, Signal Transduction, Gene Expression, Immunophenotyping, Cytokines, Interleukin-15, T-Lymphocytes, Regulatory, Forkhead Transcription Factors, Thymocytes
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