1. The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity
- Author
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Klotz, Luisa, Burgdorf, Sven, Dani, Indra, Saijo, Kaoru, Flossdorf, Juliane, Hucke, Stephanie, Alferink, Judith, Nowak, Natalija, Nowak, Nina, Beyer, Marc, Mayer, Gunter, Langhans, Birgit, Klockgether, Thomas, Waisman, Ari, Eberl, Gerard, Schultze, Joachim, Famulok, Michael, Kolanus, Waldemar, Glass, Christopher, Kurts, Christian, Knolle, Percy A, Institutes of Molecular Medicine and Experimental Immunology, Universität Bonn = University of Bonn, Department of Neurology, Department of Cellular and Molecular Medicine (CMM), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Department of Psychiatry, Institute of Molecular Psychiatry, Life and Medical Sciences Institute for Molecular Immunology, Rheinische Friedrich-Wilhelms-Universität Bonn, Life and Medical Sciences Institute for Genomics and Immunoregulation, Life and Medical Sciences Institute for Chemical Biology, Deparment of Internal Medicine, Department of Internal Medicine, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Développement des Tissus Lymphoïdes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Bonn, University of California-University of California, Johannes Gutenberg - Universität Mainz (JGU), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
- Subjects
MESH: Nuclear Receptor Subfamily 1, Group F, Member 3 ,Helper-Inducer ,Receptors, Retinoic Acid ,T-Lymphocytes ,MESH: Interleukin-17 ,Cellular differentiation ,Retinoic Acid ,Peroxisome proliferator-activated receptor ,Neurodegenerative ,Inbred C57BL ,Medical and Health Sciences ,Mice ,Interleukin 21 ,0302 clinical medicine ,Group F ,RAR-related orphan receptor gamma ,MESH: Nuclear Receptor Co-Repressor 2 ,Receptors ,2.1 Biological and endogenous factors ,Thyroid Hormone ,Immunology and Allergy ,MESH: Animals ,Aetiology ,Encephalomyelitis ,Promoter Regions, Genetic ,chemistry.chemical_classification ,Orphan receptor ,0303 health sciences ,Receptors, Thyroid Hormone ,Interleukin-17 ,Cell Differentiation ,T-Lymphocytes, Helper-Inducer ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,3. Good health ,Cell biology ,DNA-Binding Proteins ,medicine.anatomical_structure ,MESH: Repressor Proteins ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Interleukin 17 ,MESH: Cell Differentiation ,medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,Nuclear Receptor Subfamily 1 ,Member 3 ,1.1 Normal biological development and functioning ,T cell ,Immunology ,Biology ,Autoimmune Disease ,Promoter Regions ,Experimental ,03 medical and health sciences ,Genetic ,Underpinning research ,MESH: Mice, Inbred C57BL ,Internal medicine ,MESH: Promoter Regions, Genetic ,Genetics ,medicine ,Animals ,Humans ,Nuclear Receptor Co-Repressor 2 ,MESH: Receptors, Thyroid Hormone ,MESH: T-Lymphocytes, Helper-Inducer ,MESH: Encephalomyelitis, Autoimmune, Experimental ,MESH: Mice ,030304 developmental biology ,MESH: Receptors, Retinoic Acid ,MESH: Humans ,Inflammatory and immune system ,Neurosciences ,Brief Definitive Report ,Correction ,MESH: Multiple Sclerosis ,Brain Disorders ,Mice, Inbred C57BL ,PPAR gamma ,Repressor Proteins ,Endocrinology ,MESH: PPAR gamma ,Nuclear receptor ,chemistry ,MESH: DNA-Binding Proteins ,030217 neurology & neurosurgery ,Autoimmune - Abstract
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)-beta/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-beta/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.
- Published
- 2009