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Peroxisome Proliferator-Activated Receptor (PPAR) and Immunoregulation: Enhancement of Regulatory T Cells through PPAR-Dependent and -Independent Mechanisms

Elizabeth A. Wohlfert^*, Frank C. Nichols, Erin Nevius^* and Robert B. Clark^1,*

^* Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032; and Division of Periodontology, University of Connecticut Health Center, Farmington, CT 06032

Peroxisome proliferator-activated receptor (PPAR) is a nuclear hormone receptor primarily characterized for its effect on insulin metabolism. PPAR ligands, used to treat human type 2 diabetes, also down-regulate most immune system cells including APCs and pathogenic T cells. These effects putatively underlie the efficacy of PPAR ligands in treating animal models of autoimmunity, leading to projections of therapeutic potential in human autoimmunity. However, the relationship between PPAR ligands and CD4⁺CD25⁺ regulatory T cells (Tregs) has not been examined. Specifically, no studies have examined the role of Tregs in mediating the in vivo immunoregulatory effects of PPAR ligands, and there have been no investigations of the use of PPAR ligands to treat autoimmunity in the absence of Tregs. We now characterize the novel relationship between ciglitazone, a thiazolidinedione class of PPAR ligand, and both murine natural Tregs (nTregs) and inducible Tregs (iTregs). In vitro, ciglitazone significantly enhances generation of iTregs in a PPAR-independent manner. Surprisingly, and contrary to the current paradigm, we find that, in a model of graft-vs-host disease, the immunotherapeutic effect of ciglitazone requires the presence of nTregs that express PPAR. Overall, our results indicate that, unlike its down-regulatory effect on other cells of the immune system, ciglitazone has an enhancing effect on both iTregs and nTregs, and this finding may have important implications for using PPAR ligands in treating human autoimmune disease.

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 Address correspondence and reprint requests to Dr. Robert B. Clark, Department of Immunology and Department of Medicine, University of Connecticut Health Center, Farmington, CT 06032. E-mail address: rclark{at}nso2.uchc.edu

² Abbreviations used in this paper: PPAR, peroxisome proliferator-activated receptor; Treg, regulatory T cell; nTreg, natural Treg; iTreg, inducible Treg; Teff, T effector cell; GVHD, graft-vs-host disease; WT, wild type; rh, recombinant human; HPRT, hypoxanthine phosphoribosyltransferase.

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