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IL-2, -7, and -15, but Not Thymic Stromal Lymphopoeitin, Redundantly Govern CD4⁺Foxp3⁺ Regulatory T Cell Development¹

Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455

Common chain (c)-receptor dependent cytokines are required for regulatory T cell (Treg) development as c^–/– mice lack Tregs. However, it is unclear which 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 CD4⁺Foxp3⁺ Tregs in the thymus express the IL-2Rβ, IL-4R, IL-7R, IL-15R, and IL-21R chains, but not the IL9R or TSLPR 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^–/– x IL-7R^–/– and IL-2Rβ^–/– x IL-4R^–/– mice. We found that IL-2Rβ^–/– x IL-7R^–/– mice were devoid of Tregs thereby recapitulating the phenotype observed in c^–/– mice; in contrast, the phenotype observed in IL-2Rβ^–/– x IL-4R^–/– 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-7R and IL-15R 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 and IL-15R chains are up-regulated and allow for IL-7 and IL-15 to partially compensate for loss of IL-2.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a Pew Scholar Award, a Cancer Research Institute Investigator Award, a Leukemia and Lymphoma Society Scholar Award, and by National Institutes of Health Grant AI061165 to M.A.F. K.B.V. was supported by a Supplement to Promote Diversity in Health-Related Research.

² Current address: Integrated Department of Immunology, National Jewish Medical and Research Center, 1400 Jackson Street, K512C, Denver, CO 80206.

³ Address correspondence and reprint requests to Dr. Michael A. Farrar, Center for Immunology, University of Minnesota, 312 Church Street SE, 6-116 Nils Hasselmo Hall, Minneapolis, MN 55455. E-mail address: farra005{at}tc.umn.edu

⁴ Abbreviations used in this paper: Treg, regulatory T cell; c, common gamma chain; p-STAT5, phospho-STAT5; LMC, littermate control; TSLP, thymic stromal lymphopoietin.

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