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

Kieng B. Vang, Jianying Yang, Shawn A. Mahmud, Matthew A. Burchill, Amanda L. Vegoe, Michael A. Farrar

Research output: Contribution to journalArticle

160 Scopus citations

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-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.

Original languageEnglish (US)
Pages (from-to)3285-3290
Number of pages6
JournalJournal of Immunology
Volume181
Issue number5
DOIs
StatePublished - Sep 1 2008

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