Human regulatory T-cell development is dictated by Interleukin-2 and -15 expressed in a non-overlapping pattern in the thymus. (January 2015)

• Record Type: Journal Article
• Authors: Caramalho, Iris; Nunes-Silva, Vânia; Pires, Ana R.; Mota, Catarina; Pinto, Ana I.; Nunes-Cabaço, Helena; Foxall, Russell B.; Sousa, Ana E.
• Is Part Of: Journal of autoimmunity. Volume 56(2015)
• Page Start: 98
• Page End: 110
• Publication Date: 2015-01
• Subjects: Regulatory T cells -- Immune tolerance -- FOXP3 -- Human T-cell development -- Common gamma-chain cytokines; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2014.11.002
• Languages: English
• ISSNs: 0896-8411

Abstract

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. Highlights: The key γC cytokines for human thymic Treg development are IL-2 and IL-15. IL-2 and IL-15 drive human thymocyte precursor differentiation into Treg. IL-2 and IL-15 enhance proliferation and survival of differentiated FOXP3 + thymocytes. Human thymus features a non-overlapping pattern of IL-2 and IL-15 production. Targeting thymic Tregs with IL-2 or IL-15, a therapeutic option for autoimmunity.