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

Research output: Contribution to journalArticle

183 Citations (Scopus)

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.
LanguageEnglish
Pages2079-2089
Number of pages10
JournalJournal of Experimental Medicine
Volume206
DOIs
Publication statusPublished - 2009

Fingerprint

PPAR gamma
Cytoplasmic and Nuclear Receptors
Autoimmunity
T-Lymphocytes
Multiple Sclerosis
Transforming Growth Factor beta
Autoimmune Diseases
Interleukin-6
Th17 Cells
Thyroid Hormone Receptors
Co-Repressor Proteins
Retinoic Acid Receptors
Interleukin-17
Retinoids
Regulatory T-Lymphocytes
Helper-Inducer T-Lymphocytes
Transcription Factors
Ligands

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. / The nuclear receptor PPAR gamma selectively controls TH17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. In: Journal of Experimental Medicine. 2009 ; Vol. 206. pp. 2079-2089.
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The nuclear receptor PPAR gamma selectively controls TH17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. / Klotz, L.; Burgdorf, S.; Dani, I.; Saijo, K.; Flossdorf, J.; Hucke, S.; Alferink, J.; Novak, N.; Mayer, G.

In: Journal of Experimental Medicine, Vol. 206, 2009, p. 2079-2089.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The nuclear receptor PPAR gamma selectively controls TH17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity

AU - Klotz, L.

AU - Burgdorf, S.

AU - Dani, I.

AU - Saijo, K.

AU - Flossdorf, J.

AU - Hucke, S.

AU - Alferink, J.

AU - Novak, N.

AU - Mayer, G.

N1 - Strathprints' policy is to record up to 8 authors per publication, plus any additional authors based at the University of Strathclyde. More authors may be listed on the official publication than appear in the Strathprints' record.

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - aryl-hydrocarbon receptor

KW - proinflammatory il-17(+)

KW - multiple-sclerosis

KW - lipid-metabolism

KW - retinoic acid

KW - t-h-17 cells

KW - tgf-beta

KW - inflammation

KW - encephalomyelitis

KW - t(h)17

UR - http://dx.doi.org/10.1084/jem.20082771

U2 - 10.1084/jem.20082771

DO - 10.1084/jem.20082771

M3 - Article

VL - 206

SP - 2079

EP - 2089

JO - Journal of Experimental Medicine

T2 - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

ER -