1. The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity
- Author
-
Klotz, Luisa, Burgdorf, Sven, Dani, Indra, Saijo, Kaoru, Flossdorf, Juliane, Hucke, Stephanie, Alferink, Judith, Novak, Natalija, Beyer, Marc, Mayer, Gunter, Langhans, Birgit, Klockgether, Thomas, Waisman, Ari, Eberl, Gerard, Schultze, Joachim, Famulok, Michael, Kolanus, Waldemar, Glass, Christopher, Kurts, Christian, and Knolle, Percy A
- Subjects
Neurosciences ,Neurodegenerative ,Autoimmune Disease ,Multiple Sclerosis ,Genetics ,Brain Disorders ,Underpinning research ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Animals ,Cell Differentiation ,DNA-Binding Proteins ,Encephalomyelitis ,Autoimmune ,Experimental ,Humans ,Interleukin-17 ,Mice ,Mice ,Inbred C57BL ,Nuclear Receptor Co-Repressor 2 ,Nuclear Receptor Subfamily 1 ,Group F ,Member 3 ,PPAR gamma ,Promoter Regions ,Genetic ,Receptors ,Retinoic Acid ,Receptors ,Thyroid Hormone ,Repressor Proteins ,T-Lymphocytes ,Helper-Inducer ,Medical and Health Sciences ,Immunology - 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