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

Common gamma chain (gamma c)-receptor dependent cytokines are required for regulatory T cell (Treg) development as gamma c(-1-) mice lack Tregs. However, it is unclear which gamma c-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 CD(4+)Foxp(3+) Tregs in the thymus express the IL-2R beta, IL-4R alpha, IL-7R alpha, IL-15R alpha, and IL-21R alpha chains, but not the IL9R alpha or TSLPR alpha 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-2R beta(-/-) X IL-7R alpha(-/-) and IL-2R beta(-/-) x IL-4R alpha(-/-) mice. We found that IL-2R beta(-/-) x IL-7R alpha(-/-) mice were devoid of Tregs thereby recapitulating the phenotype observed in gamma c(-/-) mice; in contrast, the phenotype observed in IL-2R beta(-/-) x IL-4R alpha(-/-) mice was comparable to that seen in IL-2R beta(-/-) mice. Finally, we observed that Tregs from both IL-2(-/-) and IL-2R beta(-/-) mice show elevated expression of IL-7Ra and IL-15Ra 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-7R alpha and IL-15R alpha chains are up-regulated and allow for IL-7 and IL-15 to partially compensate for loss of IL-2.