IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4⁺Foxp3⁺ regulatory T cell development

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-7R, 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-2RR^-/- IL-7Rα^-/- and IL-2Rβ^-/- IL-4Rβ ^-/- mice. We found that IL-2Rβ^-/- X IL-7Rα^-/- mice were devoid of Tregs thereby recapitulating the phenotype observed in γc^-/- mice; in contrast, the phenotype observed in IL-2Rβ^-/- X 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.