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Cutting Edge: Foxp3⁺CD4⁺CD25⁺ Regulatory T Cells Induced by IL-2 and TGF-β Are Resistant to Th17 Conversion by IL-6¹

Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine at University of Southern California, Los Angeles, CA 90033

TGF-β has pleiotropic effects on T cell differentiation that are determined by other cytokines in the local environment. Whereas IL-2 and TGF-β induce naive T cells to become forkhead/winged helix transcription factor (Foxp3) positive regulatory cells (iTregs), the combination of IL-6 and TGF-β induces IL-17-producing cells (Th17). Moreover, IL-6 can use TGF-β produced by thymus-derived natural regulatory T cells (nTregs) to convert them to Th17 cells. In this study, we report a major difference between iTregs and nTregs. Treatment of iTregs with IL-6 did not affect Foxp3 expression, and their suppressive activity in vitro and in vivo was intact. To explain this difference between nTregs and iTregs, we found that IL-2 and TGF-β down-regulate IL-6 receptor expression and IL-6 signaling. The resistance of iTregs to Th17 conversion suggests that they can function more effectively than nTregs in an inflammatory milieu and emphasizes the central role of IL-2 in combination with TGF-β to maintain immunologic 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 grants from the Arthritis National Research Foundation, Clinical Research Feasibility Fund, and James H. Zumberge Faculty Research and Innovation Fund (to S.G.Z.); the Arthritis Foundation (to S.G.Z. and D.A.H.); and ExCell Therapeutics, Nora Eccles Treadwell Foundation, and BD Biosciences (to D.A.H.).

² Address correspondence and reprint request to: Dr. David Horwitz, 2011 Zonal Avenue, Hoffman Medical Research Building, Room 711, Los Angeles, CA 90033. E-mail address: dhorwitz{at}usc.edu or Dr. Song Guo Zheng, 2011 Zonal Avenue, Hoffman Medical Research Building, Room 710A, Los Angeles, CA 90033. E-mail address: szheng{at}usc.edu

³ Abbreviations used in this paper: Foxp3, forkhead/winged helix transcription factor; Treg, regulatory T cell; nTreg, natural CD4⁺CD25⁺ Treg; iTreg, CD4⁺CD25⁺ Treg generated ex vivo with IL-2 and TGF-β; GVHD, graft-versus-host disease.