The Journal of Experimental Medicine
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doi:10.1084/jem.20082771
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© Klotz et al.
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BRIEF DEFINITIVE REPORT

 The nuclear receptor PPAR{gamma} selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity

Luisa Klotz1,2, Sven Burgdorf1, Indra Dani1, Kaoru Saijo9, Juliane Flossdorf1, Stephanie Hucke1, Judith Alferink3,4, Natalija Novak5, Marc Beyer6, Gunter Mayer7, Birgit Langhans8, Thomas Klockgether2, Ari Waisman10, Gerard Eberl11, Joachim Schultze6, Michael Famulok7, Waldemar Kolanus5, Christopher Glass9, Christian Kurts1, and Percy A. Knolle1

1 Institutes of Molecular Medicine and Experimental Immunology; 2 Department of Neurology; 3 Department of Psychiatry and 4 Institute of Molecular Psychiatry; Life and Medical Sciences Institute for 5 Molecular Immunology, for 6 Genomics and Immunoregulation, and for 7 Chemical Biology; and 8 Department of Internal Medicine, University of Bonn, Bonn 53105, Germany
9 Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093
10 Department of Internal Medicine, University of Mainz, Mainz 55131, Germany
11 Institute Pasteur, Laboratory of Lymphoid Tissues, Centre National de la Recherche Scientifique URA1961, Paris 75724, France

CORRESPONDENCE Percy Knolle: percyknolle{at}gmail.com

T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-β/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor–related orphan receptor {gamma}t (ROR{gamma}t). We identify the nuclear receptor peroxisome proliferator–activated receptor {gamma} (PPAR{gamma}) as a key negative regulator of human and mouse Th17 differentiation. PPAR{gamma} activation in CD4+ T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPAR{gamma} involved inhibition of TGF-β/IL-6–induced expression of ROR{gamma}t in T cells. Pharmacologic activation of PPAR{gamma} prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the ROR{gamma}t promoter in T cells, thus interfering with ROR{gamma}t transcription. Both T cell–specific PPAR{gamma} knockout and endogenous ligand activation revealed the physiological role of PPAR{gamma} for continuous T cell–intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4+ T cells from healthy controls and MS patients were strongly susceptible to PPAR{gamma}-mediated suppression of Th17 differentiation. In summary, we report a PPAR{gamma}-mediated T cell–intrinsic molecular mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacologic modulation. We therefore propose that PPAR{gamma} represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.

Abbreviations used: ChIP, chromatin immunoprecipitation; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; HC, healthy control; HODE, hydroxyoctadecadienoic acid; MS, multiple sclerosis; NCoR, nuclear corepressor; PIO, pioglitazone; PPAR {gamma}, peroxisome proliferator–activated receptor {gamma}; PPRE, PPAR response element; RA, retinoic acid; ROR{gamma}t, RA receptor–related orphan receptor {gamma}t; SMRT, silencing mediator for retinoid and thyroid hormone receptors.

© 2009 Klotz et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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