The nuclear receptor PPAR gamma selectively controls TH17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity

L. Klotz, S. Burgdorf, I. Dani, K. Saijo, J. Flossdorf, S. Hucke, J. Alferink, N. Novak, G. Mayer

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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.
Original languageEnglish
Pages (from-to)2079-2089
Number of pages10
JournalJournal of Experimental Medicine
Volume206
DOIs
Publication statusPublished - 2009

Keywords

  • aryl-hydrocarbon receptor
  • proinflammatory il-17(+)
  • multiple-sclerosis
  • lipid-metabolism
  • retinoic acid
  • t-h-17 cells
  • tgf-beta
  • inflammation
  • encephalomyelitis
  • t(h)17

Cite this

Klotz, L., Burgdorf, S., Dani, I., Saijo, K., Flossdorf, J., Hucke, S., Alferink, J., Novak, N., & Mayer, G. (2009). The nuclear receptor PPAR gamma selectively controls TH17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. Journal of Experimental Medicine, 206, 2079-2089. https://doi.org/10.1084/jem.20082771