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

• Published in: The Journal of experimental medicine Vol. 206; no. 10; pp. 2079 - 2089
• Main Authors: Klotz, Luisa, Burgdorf, Sven, Dani, Indra, Saijo, Kaoru, Flossdorf, Juliane, Hucke, Stephanie, Alferink, Judith, Nowak, Nina, Novak, Natalija, 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
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 28.09.2009; The Rockefeller University Press
• Subjects: Animals; Brief Definitive Report; Cell Differentiation; DNA-Binding Proteins; DNA-Binding Proteins - metabolism; Encephalomyelitis, Autoimmune, Experimental; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Humans; Immunology; Interleukin-17; Interleukin-17 - physiology; Life Sciences; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Multiple Sclerosis - prevention & control; Nuclear Receptor Co-Repressor 2; Nuclear Receptor Subfamily 1, Group F, Member 3; PPAR gamma; PPAR gamma - physiology; Promoter Regions, Genetic; Receptors, Retinoic Acid; Receptors, Retinoic Acid - genetics; Receptors, Thyroid Hormone; Receptors, Thyroid Hormone - genetics; Repressor Proteins; Repressor Proteins - metabolism; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Helper-Inducer - cytology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20082771

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.