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Selective Survival of Naturally Occurring Human CD4⁺CD25⁺Foxp3⁺ Regulatory T Cells Cultured with Rapamycin¹

Laura Strauss^2,*,, Theresa L. Whiteside, Ashley Knights^*, Christoph Bergmann, Alexander Knuth^* and Alfred Zippelius^2,*

^* Medical Oncology, Department of Internal Medicine, University Hospital, Zurich, Switzerland; University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213; and Department of Otorhinolaryngology, University Schleswig, Luebeck, Germany

Naturally occurring CD4⁺CD25⁺ regulatory T (nTreg) cells are essential for maintaining T cell tolerance to self Ags. We show that discrimination of human Treg from effector CD4⁺CD25⁺ non-nTreg cells and their selective survival and proliferation can now be achieved using rapamycin (sirolimus). Human purified CD4⁺CD25^high T cell subsets stimulated via TCR and CD28 or by IL-2 survived and expanded up to 40-fold in the presence of 1 nM rapamycin, while CD4⁺CD25^low or CD4⁺CD25^– T cells did not. The expanding pure populations of CD4⁺CD25^high T cells were resistant to rapamycin-accelerated apoptosis. In contrast, proliferation of CD4⁺CD25^– T cells was blocked by rapamycin, which induced their apoptosis. The rapamycin-expanded CD4⁺CD25^high T cell populations retained a broad TCR repertoire and, like CD4⁺ CD25⁺ T cells freshly obtained from the peripheral circulation, constitutively expressed CD25, Foxp3, CD62L, glucocorticoid-induced TNFR family related protein, CTLA-4, and CCR-7. The rapamycin-expanded T cells suppressed proliferation and effector functions of allogeneic or autologous CD4⁺ and CD8⁺ T cells in vitro. They equally suppressed Ag-specific and nonspecific responses. Our studies have defined ex vivo conditions for robust expansion of pure populations of human nTreg cells with potent suppressive activity. It is expected that the availability of this otherwise rare T cell subset for further studies will help define the molecular basis of Treg-mediated suppression in humans.

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 in part by a Swiss National Science Foundation special program, and a grant from the Cancer Research Institute/Ludwig Institute for Cancer Research Cancer Vaccine Collaborative, the Terry-Fox, Hanne-Liebermann, and Claudia-von-Schilling Foundation, and UBS Wealth Management. A.Z. was supported in part by the Emmy-Noether Program (Zi685-2/3) of the Deutsche Forschungsgemeinschaft. T.L.W. was supported in part by National Institutes of Health Grant PO-1 DE12321.

² Address correspondence and reprint requests to Dr. Laura Strauss, University of Pittsburgh Cancer Institute, Research Pavilion at the Hillman Cancer Center, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213-1863; E-mail address: straussl{at}upmc.edu or Dr. Alfred Zippelius, Medical Oncology, Department of Internal Medicine, University Hospital, Raemistrasse 100, 8091, Zurich, Switzerland; E-mail address: Alfred.Zippelius{at}usz.ch

³ Abbreviations used in this paper: Treg, regulatory T; nTreg, naturally occurring CD4⁺CD25⁺ Treg; GITR, glucocorticoid-induced TNFR family related protein; TT, tetanus toxoid; ANX V, annexin V; LN, lymph node; MFI, mean fluorescence intensity; PI, propidium iodine.

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