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Th3 Cells in Peripheral Tolerance. II. TGF--Transgenic Th3 Cells Rescue IL-2-Deficient Mice from Autoimmunity¹

Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

We developed a transgenic (Tg) mouse that expresses TGF- under control of the IL-2 promoter to investigate Th3 cell differentiation both in vitro and in vivo. We previously found that repetitive in vitro Ag stimulation results in constant expression of Foxp3 in TGF--Tg Th3 cells that acquire regulatory function independent of surface expression of CD25. To examine the differentiation and function of Th3 cells in vivo and to compare them with thymic-derived CD4⁺CD25⁺ regulatory T cells (Treg), we introduced the TGF- transgene into T cells of IL-2-deficient (IL-2^–/–) mice. We found that the induction, differentiation, and function of TGF--derived Foxp3⁺ Th3 cells were independent of IL-2, which differs from thymic Tregs. In an environment that lacks functional CD25⁺ thymic-derived Tregs, expression of the TGF- transgene in IL-2^–/– mice led to the induction of distinct CD25^– regulatory cells in the periphery. These cells expressed Foxp3 and efficiently controlled hyperproliferation of T cells and rescued the IL-2^–/– mouse from lethal autoimmunity. Unlike IL-2^–/– animals, TGF-/IL-2^–/– mice had normal numbers of T cells, B cells, macrophages, and dendritic cells and did not have splenomegaly, lymphadenopathy, or inflammation in multiple organs. Accumulation of Foxp3⁺ cells over time, however, was dependent on IL-2. Our results suggest that TGF--derived Foxp3⁺CD25^+/– Th3 regulatory cells represent a different cell lineage from thymic-derived CD25⁺ Tregs in the periphery but may play an important role in maintaining thymic Tregs in the peripheral immune compartment by secretion of TGF-.

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 Multiple Sclerosis Society Fellowship Grant FG1479A1/1 (to Y.C.) and by National Institutes of Health Grants AI435801 and NS38037 (to H.L.W.).

² Address correspondence and reprint requests to Dr. Howard L. Weiner, Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115. E-mail address: hweiner{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; Tg, transgenic; iTreg, induced Treg; WT, wild type; LN, lymph node; DC, dendritic cell.

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