title: 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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal. Electronic address: iriscaramalho@medicina.ulisboa.pt.
authors.forename: Iris
authors.initials: I
authors.lastname: Caramalho
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
authors.forename: Vânia
authors.initials: V
authors.lastname: Nunes-Silva
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Pires
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Mota
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Pinto
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Nunes-Cabaço
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
authors.forename: Russell B
authors.initials: RB
authors.lastname: Foxall
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
authors.forename: Ana E
authors.initials: AE
authors.lastname: Sousa
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D019409:Interleukin-15 / Q000235:genetics* / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism*
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D019409:Interleukin-15; D007376:Interleukin-2
keywords: Common gamma-chain cytokines; FOXP3; Human T-cell development; Immune tolerance; Regulatory T cells