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Plasticity of Regulatory T Cells: Subversion of Suppressive Function and Conversion to Enhancement of Lung Allergic Responses^1,2

Department of Pediatrics, Division of Cell Biology, National Jewish Medical and Research Center, Denver, CO 80206

Activation of CD4⁺CD25⁺Foxp3⁺ naturally occurring regulatory T cells (nTregs) resulting in suppression of lung allergic responses requires interaction of MHC class I on nTregs and CD8. In the absence of CD8 (CD8^–/– recipients), transferred nTregs restored airway hyperresponsiveness, eosinophilic inflammation, and IL-13 levels following allergen exposure. Enhancement of lung allergic responses was accompanied by reduced expression of Foxp3 and increased expression of IL-13 in the transferred nTregs. In CD8^–/– recipients pretreated with glucocorticoid-induced TNFR-related protein-ligand Ab, the transferred nTregs maintained high levels of Foxp3 and did not result in altered lung responses. Thus, the regulatory function of nTregs can be subverted by reducing the expression of Foxp3 and following signaling through glucocorticoid-induced TNFR-related protein are converted nTregs into IL-13-producing CD4⁺ T cells mediating lung allergic responses.

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 HL-36577 and HL-61005 and by Environmental Protection Agency Grant R825702.

² The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

³ Address correspondence and reprint requests to Dr. Erwin W. Gelfand, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail address: gelfande{at}njc.org

⁴ Abbreviations used in this paper: nTregs, naturally occurring CD4⁺CD25⁺ T cells; AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; C_dyn, dynamic compliance; GITR, glucocorticoid-induced TNFR-related protein; MCh, methacholine; PAS, periodic acid-Schiff; R_L, lung resistance; WT, wild type; GITR-L, GITR ligand; MHC I, MHC class I; Treg, regulatory T cell.

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