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* Tyrolean Cancer Research Institute,
Internal Medicine V, Hematology and Oncology, and
Internal Medicine IV, Nephrology and Hypertension, Innsbruck Medical University, Innsbruck, Austria;
Division of Hematology and Oncology, Department of Medicine,
¶ Department of Biology, and
|| Department of Pathology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; and
# Max Planck Institute for Biochemistry, Martinsried, Germany
CD4+CD25+ regulatory T cell (Treg) entry into secondary lymphoid organs and local expansion is critical for their immunosuppressive function. Long-term application of the sphingosine-1 phosphate receptor agonist FTY720 exerts pleiotropic anti-inflammatory effects, whereas short-term FTY720 boosts antiviral immunity. In this study, we provide evidence that FTY720 potently inhibits Treg proliferation in vitro and in vivo without affecting their viability, phenotype, or in vitro immunosuppression. In contrast, adoptively transferred Treg exposed ex vivo to FTY720 lost their protective effects in murine models of acute glomerulonephritis and acute graft-vs-host disease. On a cellular level, FTY720 inhibits IL-2-induced STAT-5 phosphorylation, paralleled by a loss of FoxP3 expression during Treg expansion in vitro. Notably, loss of in vivo immunosuppression is not due to impaired migration to or localization within secondary lymphoid organs. We could even show a selective trapping of adoptively transferred Treg in inflammatory lymph nodes by FTY720. Finally, Treg isolated from animals systemically exposed to FTY720 also exhibit a significantly impaired proliferative response upon restimulation when compared with Treg isolated from solvent-treated animals. In summary, our data suggest that sphingosine-1 phosphate receptor-mediated signals induced by FTY720 abrogate their in vivo immunosuppressive potential by blocking IL-2 induced expansion, which is indispensable for their in vivo immunosuppressive activity.
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 The project was supported by the Tiroler Landeskrankenanstalten and the Medizinischer Forschungsfonds Tirol. M.S. was supported by the Peter Hans Hofschneider Foundation for Experimental Biomedicine.
A.M.W. designed the study, performed research, analyzed data, and wrote the manuscript. K.H. and R.Z. performed research and analyzed data. C.D., L.M., and M.S. performed research. A.R.R. and G.G. provided infrastructure. U.V.G. conducted blind histopathology scoring. D.W. designed the study, analyzed data, and wrote the manuscript.
2 Parts of this project have been presented at the World Immune Regulation Meeting II in Davos, Switzerland, March 16–20, 2008, and at the American Society of Hematology 50th Annual Meeting and Exposition in San Francisco, CA, December 6–9, 2008.
3 Address correspondence and reprint requests to Dr. Maria Wolf, Tyrolean Cancer Research Institute, Innsbruck Medical University, Innrain 66, 6020 Innsbruck, Austria. E-mail address: maria.wolf{at}i-med.ac.at
4 Abbreviations used in this paper: Treg, regulatory T cell; GBM, glomerular basement membrane; GN, glomerulonephritis; GvHD, graft-versus-host disease; aGvHD, acute GvHD; FTY-Treg, FTY720-treated Treg; LN, lymph node; PAS, periodic acid Schiff; SLO, secondary lymphoid organ; solv-Treg, solvent-treated Treg; S1P, sphingosine-1 phosphate; Tconv, conventional T cell.
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