title: The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity.
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.
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, Department of Neurology, University of Bonn, Bonn 53105, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Klotz
authors.forename: Sven
authors.initials: S
authors.lastname: Burgdorf
authors.forename: Indra
authors.initials: I
authors.lastname: Dani
authors.forename: Kaoru
authors.initials: K
authors.lastname: Saijo
authors.forename: Juliane
authors.initials: J
authors.lastname: Flossdorf
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hucke
authors.forename: Judith
authors.initials: J
authors.lastname: Alferink
authors.forename: Nina
authors.initials: N
authors.lastname: Nowak
authors.forename: Natalija
authors.initials: N
authors.lastname: Novak
authors.forename: Marc
authors.initials: M
authors.lastname: Beyer
authors.forename: Gunter
authors.initials: G
authors.lastname: Mayer
authors.forename: Birgit
authors.initials: B
authors.lastname: Langhans
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Gerard
authors.initials: G
authors.lastname: Eberl
authors.forename: Joachim
authors.initials: J
authors.lastname: Schultze
authors.forename: Michael
authors.initials: M
authors.lastname: Famulok
authors.forename: Waldemar
authors.initials: W
authors.lastname: Kolanus
authors.forename: Christopher
authors.initials: C
authors.lastname: Glass
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000517:prevention & control*; D056985:Nuclear Receptor Co-Repressor 2; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D047495:PPAR gamma / Q000502:physiology*; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*
chemical_list: D004268:DNA-Binding Proteins; D020381:Interleukin-17; C539130:NCOR2 protein, human; C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D047495:PPAR gamma; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; C539901:Rorc protein, mouse