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Anti-Inflammatory Effects of FTY720 against Viral-Induced Immunopathology: Role of Drug-Induced Conversion of T Cells to Become Foxp3⁺ Regulators¹

Comparative and Experimental Medicine, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996-0845

FTY720 has been used to control inflammatory lesions, but the mechanisms by which the drug acts in vivo are poorly understood. Such mechanisms may result primarily from effects on lymphocyte and dendritic cell homing to lymphoid and inflammatory sites. We demonstrate that FTY720 may also act by causing the conversion of TCR-stimulated nonregulatory CD4⁺ T cells to Foxp3⁺CD4⁺ regulatory T cells and by enhancing their suppressive activity. In a model in which mice were ocularly infected with HSV, daily treatment with FTY720 resulted in significantly diminished ocular lesions. The treated animals showed increased frequencies of Foxp3⁺ T cells in lymphoid organs and at two inflammatory sites, namely cornea and trigeminal ganglia. In a second series of experiments, immunized DO11.10RAG2^–/– animals, normally lacking endogenous Foxp3⁺ T cells, that were given FTY720 treatment developed high frequencies of Foxp3⁺ regulatory T cells in lymph nodes. Some converted cells persisted in treated animals for several weeks after drug administration was discontinued. Finally, FTY720 could effectively induce Foxp3-expressing cells from Foxp3^– cells in vitro, an effect inhibited by anti-TGF-β or the proinflammatory cytokine IL-6. Accordingly, the anti-inflammatory effects of FTY720 could be mediated at least in part by its ability to cause the conversion of Ag-stimulated conventional T cells to become Foxp3⁺ regulators. The use of FTY720 along with Ag administration could represent a useful therapeutic means to selectively expand Ag-specific regulators, which could be valuable in many clinical situations such as allotransplants, some autoimmunities, as well as with some chronic infections.

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 supported by the National Institute of Allergy and Infectious Diseases Grant AI 063365 and the National Institutes of Health Grant EY 05093.

² Address correspondence and reprint requests to Dr. Barry T. Rouse, M409, Walters Life Sciences Building, Department of Pathobiology, University of Tennessee, 1414 Comberland Avenue, Knoxville, TN 37996-0845. E-mail addresses: btr{at}utk.edu and ss1{at}utk.edu

³ Abbreviations used in this paper: S1P, sphingosine-1-phosphate; BW, body weight; DPI, days postinfection; GITR, glucocorticoid-induced TNF receptor; LN, lymph node; PI, postinfection; SK, stromal keratitis; TG, trigeminal ganglia; Treg, regulatory T cell.

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