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T Cell-Transgenic Mice1
Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
TGF-
has been shown to be critical in the generation of CD4+CD25+Foxp3+ regulatory T cells (Tregs). Because Th3 cells produce large amounts of TGF-, we asked whether induction of Th3 cells in the periphery was a mechanism by which CD4+CD25+ Tregs were induced in the peripheral immune compartment. To address this issue, we generated a TGF-1-transgenic (Tg) mouse in which TGF- is linked to the IL-2 promoter and T cells transiently overexpress TGF- upon TCR stimulation but produce little or no IL-2, IL-4, IL-10, IL-13, or IFN-
. Naive TGF--Tg mice are phenotypically normal with comparable numbers of lymphocytes and thymic-derived Tregs. We found that repeated antigenic stimulation of pathogenic myelin oligodendrocyte glycoprotein (MOG)-specific CD4+CD25– T cells from TGF- Tg mice crossed to MOG TCR-Tg mice induced Foxp3 expression in both CD25+ and CD25– populations. Both CD25 subsets were anergic and had potent suppressive properties in vitro and in vivo. Furthermore, adoptive transfer of these induced regulatory CD25+/– T cells suppressed experimental autoimmune encephalomyelitis when administrated before disease induction or during ongoing experimental autoimmune encephalomyelitis. The suppressive effect of TGF- on T cell responses was due to the induction of Tregs and not to the direct inhibition of cell proliferation. The differentiation of Th3 cells in vitro was TGF- dependent as anti-TGF- abrogated their development. Thus, Ag-specific TGF--producing Th3 cells play a crucial role in inducing and maintaining peripheral tolerance by driving the differentiation of Ag-specific Foxp3+ regulatory cells in the periphery.
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; EAE, experimental autoimmune encephalomyelitis; Tg, transgenic; MOG, myelin oligodendrocyte glycoprotein; 7-AAD, 7-aminoactinomycin D; WT, wild type.
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