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Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136
IL-2 contributes to the production, function, and homeostasis of CD4+CD25+ Treg cells. However, it remains uncertain whether IL-2 is essential for the development of Treg cells in the thymus, their homeostasis in the periphery, or both. The present study was undertaken to investigate the contribution of IL-2 during thymic Treg cell development and its maintenance in peripheral immune tissue. Relying on genetic mouse models where IL-2R signaling was either completely blocked or selectively inhibited in peripheral CD4+CD25+ Treg cells, we show that the IL-2/IL-2R interaction is active in the thymus at the earliest stage of the development of Treg cells to promote their expansion and to up-regulate Foxp3 and CD25 to normal levels. Furthermore, CD4+CD25+Foxp3+ Treg cells with impaired IL-2-induced signaling persist in the periphery and control autoimmunity without constant thymic output. These peripheral Treg cells with poor responsiveness to IL-2 exhibited slower growth and extended survival in vivo, somewhat lower suppressive activity, and poor IL-2-dependent survival in vitro. Mixed thymic and bone marrow chimeric mice showed that wild-type-derived Treg cells were substantially more effective in populating peripheral immune tissue than Treg cells with impaired IL-2 signaling. Collectively, these data support the notion that normally IL-2 is a dominant mechanism controlling the number of thymic and peripheral Treg cells.
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 by National Institutes of Health Grants CA45957 and AI055815.
2 Address correspondence and reprint requests to Dr. Thomas R. Malek, University of Miami Miller School of Medicine, Department of Microbiology and Immunology, R138, 1600 Northwest 10th Avenue, Miami, FL 33146. E-mail address: tmalek{at}med.miami.edu
3 Abbreviations used in this paper: Treg, T regulatory cell; 7-AAD, 7-aminoactinomycin; DP, double positive; Foxp3, Forkhead box P3 transcription factor; GITR, glucocorticoid-induced TNFR; Gy, gray; LN, lymph node; HSA, heat-stable Ag; MFI, mean fluorescence intensity; LT
, lymphotoxin-; SP, single positive; Tg–/–, thymic-specific expression of IL-2R in IL-2R–/– mice; WT, wild type.
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