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A Function for IL-7R for CD4⁺CD25⁺Foxp3⁺ T Regulatory Cells¹

Allison L. Bayer^2,*,, Joon Youb Lee, Anabel de la Barrera, Charles D. Surh and Thomas R. Malek^*,

^* Department of Microbiology and Immunology and Diabetes Research Institute, Miller School of Medicine, University of Miami, FL 33136; and Department of Immunology, Scripps Research Institute, La Jolla, CA 92037

The IL-2/IL-2R interaction is important for development and peripheral homeostasis of T regulatory (T_reg) cells. IL-2- and IL-2R-deficient mice are not completely devoid of Foxp3⁺ cells, but rather lack population of mature CD4⁺CD25⁺Foxp3^high T_reg cells and contain few immature CD4⁺CD25^–Foxp3^low T cells. Interestingly, common chain (c) knockout mice have been shown to have a near complete absence of Foxp3⁺ T_reg cells, including the immature CD25^–Foxp3^low subset. Therefore, other c-cytokine(s) must be critically important during thymic development of CD4⁺CD25⁺Foxp3⁺ T_reg cells apart from the IL-2. The present study was undertaken to determine whether the c-cytokines IL-7 or IL-15 normally contribute to expression of Foxp3 and T_reg cell production. These studies revealed that mice double deficient in IL-2Rβ and IL-7R contained a striking lack in the CD4⁺Foxp3⁺ population and the T_reg cell defect recapitulated the c knockout mice. In the absence of IL-7R signaling, IL-15/IL-15R interaction is dispensable for the production of CD4⁺CD25⁺Foxp3⁺ T_reg cells, indicating that normal thymic T_reg cell production likely depends on signaling through both IL-2 and IL-7 receptors. Selective thymic reconstitution of IL-2Rβ in mice double deficient in IL-2Rβ and IL-7R established that IL-2Rβ is dominant and sufficient to restore production of T_reg cells. Furthermore, the survival of peripheral CD4⁺Foxp3^low cells in IL-2Rβ^–/– mice appears to depend upon IL-7R signaling. Collectively, these data indicate that IL-7R signaling contributes to T_reg cell development and peripheral homeostasis.

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 R01 CA45957 and AI055815 and Juvenile Diabetes Research Foundation International 4-2004-361, Juvenile Diabetes Research Foundation Center at the University of Miami-Diabetes Research Institute.

² Address correspondence and reprint requests to Dr. Allison L. Bayer, Miller School of Medicine University of Miami, Departments of Microbiology and Immunology and Diabetes Research Institute, 1450 Northwest 10th Avenue, Miami, FL 33136. E-mail address: abayer{at}med.miami.edu

³ Abbreviations used in this paper: T_reg, T regulatory cell; DKO, double knockout; SP, single positive; DP, double positive; TG, thymic transgene; TSLP, thymic stromal lymphopoietin; WT, wild type; c, common chain.