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Outgrowth of CD4^low/negCD25⁺ T Cells with Suppressor Function in CD4⁺CD25⁺ T Cell Cultures upon Polyclonal Stimulation Ex Vivo¹

Christine Vogtenhuber^*, Matthew J. O'Shaughnessy^*, Dario A. A. Vignali and Bruce R. Blazar^2,*

^* University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, MN 55455; and Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105

CD4⁺CD25⁺ regulatory T cells (Tregs) play an essential role in controlling autoimmunity and allograft rejection. Several ex vivo activation and expansion protocols have been developed to amplify cell numbers and suppressor function of murine and human Tregs. We demonstrate in this study that ex vivo activation and expansion of murine Tregs resulted in an enrichment of a CD4^low/negCD25⁺ T cell population that was more than 20-fold more potent than expanded conventional Tregs in suppressing an in vitro CD4⁺CD25^– T cell response to allo-Ag. The generation of CD4^low/negCD25⁺ T cells was independent of the presence of Tregs in the culture, and suppressor function was acquired only after activation and expansion. CD4^low/negCD25⁺ T cells expressed either an β or TCR, had an activated phenotype, and did not express the transcription factor FoxP3. Despite expressing the cell surface Ags lymphocyte activation gene-3 (CD223) and CD103, neither was essential for suppressor cell function. Suppression by CD4^low/negCD25⁺ T cells was prevented by a semipermeable membrane and was independent of IL-10 and TGF-β. In summary, we describe in this study CD4^low/negCD25⁺ FoxP3^neg T cells with highly potent suppressor cell function derived from cultures of an enriched population of CD4⁺CD25⁺ T cells that may contribute to the suppressor activity of ex vivo expanded bone fide 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 National Institutes of Health Grants P01 AI056299, R01 AI034495, and R37 HL56067 and the Children’s Cancer Research Fund (to C.V. and B.R.B.).

² Address correspondence and reprint requests to Dr. Bruce R. Blazar, University of Minnesota, 460F CCRB, 425 East River Road, Minneapolis, MN 55455. E-mail address: blaza001{at}umn.edu

³ Abbreviations used in this paper: Treg, CD4⁺CD25⁺ regulatory T cell; DN, double negative; GVHD, graft-vs-host disease; LAG-3, lymphocyte activation gene-3; neg, negative; wt, wild type.

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The JI 2008 181: 8185-8186. [Full Text]  

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