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-Dependent STAT5 Activation Is Required for the Development of Foxp3+ Regulatory T Cells1
* Department of Laboratory Medicine and Pathology and Department of Pediatrics, Center for Immunology, Cancer Center and
Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455
IL-2–/– mice develop autoimmunity despite having relatively normal numbers of regulatory T cells (Tregs). In contrast, we demonstrate that IL-2–/– x IL-15–/– and IL-2R
–/– mice have a significant decrease in Treg numbers. Ectopic expression of foxp3 in a subset of CD4+ T cells rescued Treg development and prevented autoimmunity in IL-2R–/– mice, suggesting that IL-2R-dependent signals regulate foxp3 expression in Tregs. Subsequent analysis of IL-2R-dependent signal transduction pathways established that the transcription factor STAT5 is necessary and sufficient for Treg development. Specifically, T cell-specific deletion of STAT5 prevented Treg development; conversely, reconstitution of IL-2R–/– mice with bone marrow cells expressing an IL-2R mutant that exclusively activates STAT5 restored Treg development. Finally, STAT5 binds to the promoter of the foxp3 gene suggesting that IL-2R-dependent STAT5 activation promotes Treg differentiation by regulating expression of foxp3.
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 (to M.A.F.), a Cancer Investigator Award (to M.A.F.), and by National Institutes of Health Grants AI061165 (to M.A.F.) and HL63452, AI34495, and HL56067 (to B.R.B.). M.A.B. is supported by a National Institutes of Health Training Grant (2T32-AI07313) and a gift from the estate of Eli and Dorothy Rosen and Bernard Collins.
2 M.A.B. and J.Y. contributed equally to the results presented here.
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; WT, wild type; LN, lymph node; ChIP, chromatin immunoprecipitation; LMC, littermate control mice; 
c, common -chain; DN, double negative.
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