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Cutting Edge: Foxp3-Mediated Induction of Pim 2 Allows Human T Regulatory Cells to Preferentially Expand in Rapamycin¹

Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Addition of rapamycin to cultures of expanding natural CD4⁺CD25⁺Foxp3⁺ T regulatory cells (Tregs) helps maintain their suppressive activity, but the underlying mechanism is unclear. Pim 2 is a serine/threonine kinase that can confer rapamycin resistance. Unexpectedly, pim 2 was found to be constitutively expressed in freshly isolated, resting Tregs, but not in CD4⁺CD25^– T effector cells. Introduction of Foxp3, but not Foxp32, into effector T cells induced pim 2 expression and conferred preferential expansion in the presence of rapamycin, indicating that Foxp3 can regulate pim 2 expression. Finally, we determined there is a positive correlation between Treg expansion and Foxp3 expression in the presence of rapamycin. Together, these results indicate that Tregs are programmed to be resistant to rapamycin, providing further rationale for why this immunosuppressive drug should be used in conjunction with expanded Tregs.

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 Juvenile Diabetes Research Foundation (JDRF) Collaborative Center for Cell Therapy, the JDRF Autoimmunity Center on Cord Blood Therapy for Diabetes, and National Institutes of Health Grants R01 CA105216 and R01 AI057838. S.B. received support from National Institutes of Health Grant T32 CA101968.

² Address correspondence and reprint requests to Dr. James L. Riley, Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 556 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia PA 19104-6160. E-mail address: rileyj{at}mail.med.upenn.edu

³ Abbreviations used in this paper: Treg, T regulatory cell; aAPC, artificial APC; mTOR, mammalian target of rapamycin; YFP, yellow fluorescent protein.

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