IL-2, -7, and -15, but Not Thymic Stromal Lymphopoeitin, Redundantly Govern CD4+Foxp3+ Regulatory T Cell Development

Abstract

Common γ chain (γc)-receptor dependent cytokines are required for regulatory T cell (Treg) development as γc−/− mice lack Tregs. However, it is unclear which γc-dependent cytokines are involved in this process. Furthermore, thymic stromal lymphopoietin (TSLP) has also been suggested to play a role in Treg development. In this study, we demonstrate that developing CD4+Foxp3+ Tregs in the thymus express the IL-2Rβ, IL-4Rα, IL-7Rα, IL-15Rα, and IL-21Rα chains, but not the IL9Rα or TSLPRα chains. Moreover, only IL-2, and to a much lesser degree IL-7 and IL-15, were capable of transducing signals in CD4+Foxp3+ Tregs as determined by monitoring STAT5 phosphorylation. Likewise, IL-2, IL-7, and IL-15, but not TSLP, were capable of inducing the conversion of CD4+CD25+Foxp3− thymic Treg progenitors into CD4+Foxp3+ mature Tregs in vitro. To examine this issue in more detail, we generated IL-2Rβ−/− × IL-7Rα−/− and IL-2Rβ−/− × IL-4Rα−/− mice. We found that IL-2Rβ−/− × IL-7Rα−/− mice were devoid of Tregs thereby recapitulating the phenotype observed in γc−/− mice; in contrast, the phenotype observed in IL-2Rβ−/− × IL-4Rα−/− mice was comparable to that seen in IL-2Rβ−/− mice. Finally, we observed that Tregs from both IL-2−/− and IL-2Rβ−/− mice show elevated expression of IL-7Rα and IL-15Rα chains. Addition of IL-2 to Tregs from IL-2−/− mice led to rapid down-regulation of these receptors. Taken together, our results demonstrate that IL-2 plays the predominant role in Treg development, but that in its absence the IL-7Rα and IL-15Rα chains are up-regulated and allow for IL-7 and IL-15 to partially compensate for loss of IL-2.

Le renouveau de l’interleukine 2

“…Elle est à la fois un facteur de survie pour ces cellules et critique pour leur activité suppressive. Elle contribue également au développement des lymphocytes Treg dans le thymus, mais cela, de manière redondante avec d'autres cytokines (IL-7, IL-15) [19]. Son rôle sur les T conventionnels apparaît plus complexe.…”

Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15

“…The role of cytokines in development, homeostasis, and function of Tregs remains to be elucidated. IL-2 is known to be essential for Treg homeostasis and activation (58)(59)(60), and most Treg-expansion protocols make use of high concentrations (.200 U/ml) of IL-2. However, IL-2-deficient mice had normal numbers of functional Tregs (61,62), but mice lacking both IL-2 and IL-15 showed a decrease in functional Tregs (63).…”

Inflammation and Lymphopenia Trigger Autoimmunity by Suppression of IL-2–Controlled Regulatory T Cell and Increase of IL-21–Mediated Effector T Cell Expansion

“…The common g-chain cytokines IL-2, IL-7, and IL-15 are important for thymic T reg homeostasis (31,(40)(41)(42). Increased NF-kB signaling in thymocytes may function as sensor of peripheral inflammation and increase the secretion of TNF-a, inducing the development of T regs in the thymus (43).…”