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

Klotz, L., Burgdorf, S., Dani, I., Saijo, K., Flossdorf, J., Hucke, S., et al. (2009). The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. The Journal of experimental medicine, 206(10), 2079-89. doi:10.1084/jem.20082771.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-6445-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-6446-1
Genre: Journal Article

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 Creators:
Klotz, L., Author
Burgdorf, S., Author
Dani, I., Author
Saijo, K., Author
Flossdorf, J., Author
Hucke, S., Author
Alferink, J., Author
Nowak, N., Author
Beyer, M., Author
Mayer, G., Author
Langhans, B., Author
Klockgether, T., Author
Waisman, A., Author
Eberl, G., Author
Schultze, J., Author
Famulok, M.1, Author
Kolanus, W., Author
Glass, C., Author
Kurts, C., Author
Knolle, P. A., Author
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1External Organizations, ou_persistent22              

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Free keywords: Animals Cell Differentiation DNA-Binding Proteins/metabolism Encephalomyelitis, Autoimmune, Experimental/*prevention & control Humans Interleukin-17/physiology Mice Mice, Inbred C57BL Multiple Sclerosis/*prevention & control Nuclear Receptor Co-Repressor 2 Nuclear Receptor Subfamily 1, Group F, Member 3 PPAR gamma/*physiology Promoter Regions, Genetic Receptors, Retinoic Acid/genetics Receptors, Thyroid Hormone/genetics Repressor Proteins/metabolism T-Lymphocytes, Helper-Inducer/*cytology
 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.

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 Dates: 2009
 Publication Status: Published in print
 Pages: -
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 Rev. Type: -
 Identifiers: Other: 19737866
DOI: 10.1084/jem.20082771
ISSN: 1540-9538 (Electronic)
ISSN: 0022-1007 (Linking)
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Title: The Journal of experimental medicine
  Alternative Title : J. Exp. Med.
Source Genre: Journal
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Pages: - Volume / Issue: 206 (10) Sequence Number: - Start / End Page: 2079 - 89 Identifier: -