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to Convert Naive CD4+CD25– Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells1
Division of Rheumatology and Immunology, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033
IL-2 and TGF-
both have important roles in the induction and maintenance of immunologic tolerance, but whether these cytokines act separately or together to achieve this effect is poorly understood. Although others have reported that IL-2 can directly enhance forkhead box protein P3 (Foxp3) transcription factor expression by natural CD4+CD25+ regulatory T cells, in this study, we report that the role of IL-2 on the generation of peripheral regulatory CD4+ cells is indirect. Ab neutralization studies and experiments with IL-2-deficient mice have revealed that IL-2 is required for TGF- to induce naive CD4+CD25– cells to become CD25+ and express Foxp3, and develop the characteristic properties of CD4+CD25+ regulatory cells. This effect of IL-2 on the generation and expansion of these adaptive Foxp3+ regulatory cells is nonredundant, but IL-4, IL-7, and IL-15, other common 
-chain cytokines, could sustain Foxp3 expression. Because subjects with autoimmune diseases often have defects in the production of IL-2 and/or TGF-, the generation of autologous T regulatory cells ex vivo with these cytokines for transfer in vivo may have considerable therapeutic potential.
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 grants from the National Institutes of Health (Grant AI-41768; to D.A.H.); Arthritis Foundation (to D.A.H. and S.G.Z.); Nora Eccles Treadwell Foundation (to D.A.H.); Arthritis National Research Foundation (to S.G.Z.); Wright Foundation (to S.G.Z.), Clinical Research Feasibility Fund (to S.G.Z.); and James H. Zumberge Faculty Research and Innovation Fund (to S.G.Z.).
2 Current address: Division of Rheumatology, Immunology and Nephrology, Zhejiang Traditional Chinese Medicine and Western Medicine Hospital, Hangzhou, 310003, People’s Republic of China.
3 Address correspondence and reprint requests to Dr. David A. Horwitz, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, Hoffman Building 711, Los Angeles, CA 90033. E-mail address: dhorwitz{at}usc.edu
4 Abbreviations used in this paper: Treg, regulatory T; GITR, glucocorticoid-induced TNF receptor; HPRT, hypoxanthine guanine phosphoribosyl transferase; SLE, systemic lupus erythematosus.
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