The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity

Klotz, Luisa; Burgdorf, Sven; Dani, Indra; Saijo, Kaoru; Floßdorf, Juliane; Hucke, Stephanie; Alferink, Judith; Novak, Natalija; Beyer, Marc; Mayer, Günter; Langhans, Bettina; Klockgether, Thomas; Waisman, Ari; Eberl, Gérard; Schultze, Joachim L.; Famulok, Michael; Kolanus, Waldemar; Glass, Christopher K.; Kurts, Christian; Knolle, Percy A.

doi:10.1084/jem.20082771

Cited by 294 publications

(286 citation statements)

References 41 publications

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“…Differentiation was performed as described previously (33). In brief, murine CD4 + T cells were isolated (spleen and lymph node) using magnetic beads (Miltenyi; negative selection protocol).…”

Section: Murine T H Cell Differentiationmentioning

confidence: 99%

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B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

Herold

Posevitz

Chudyka

et al. 2015

The Journal of Immunology

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It is currently acknowledged that TH17 cells are critically involved in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). In this article, we demonstrate that signals delivered by the coinhibitory molecule B7-homologue 1 (B7-H1) via a B7-homologue 1 mouse-IgG2aFc (B7-H1-Ig) fusion protein nearly abolish TH17, but not TH1 and TH2, differentiation via direct interaction with the T cell. These effects were equally pronounced in the absence of programmed death-1 or B7.1 and B7.2 on the T cell side, thus providing clear evidence that B7-H1 modulates T cell differentiation via a novel receptor. Mechanistically, B7-H1 interfered with early TCR-mediated signaling and cytokine-mediated induction of the TH17-determining transcription factors retinoic acid-related orphan receptor γ t and IFN regulator factor-4 in a programmed death-1 and B7-independent fashion. In an animal model of MS, active myelin oligodendrocyte glycoprotein–induced experimental autoimmune encephalomyelitis, B7-H1-Ig exhibited a significant and long-lasting effect on disease severity upon administration during the first 5 d of the priming phase, which was accompanied by reduced TH17 responses in the periphery and within the CNS. Importantly, B7-H1-Ig was even capable of interfering with T cell encephalitogenicity when interaction with the T cells occurred after priming using an adoptive transfer experimental autoimmune encephalomyelitis model. In line with this, both naive human CD4+ T cells and differentiated TH17 effector cells from MS patients were highly sensitive toward B7-H1-Ig–mediated TH17 suppression. Together, we propose the existence of a novel B7-H1–mediated immune-regulatory pathway in T cells, which selectively limits murine and human TH17 cell responses and might be therapeutically exploited to control TH17-mediated autoimmunity.

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Section: Murine T H Cell Differentiationmentioning

confidence: 99%

“…EAE was induced in C57BL/6 mice or in PD-1 knockout mice by immunization with 50 mg MOG 35-55 as described previously (33). From the day of immunization mice received daily i.p.…”

Section: Active Mog Eaementioning

confidence: 99%

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

Herold

Posevitz

Chudyka

et al. 2015

The Journal of Immunology

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“…T-cell-specific PPARγ -/-mice were reported to exhibit enhanced disease severity in experimental autoimmune encephalomyelitis (EAE) with increased infiltration of Th17 cells into the central nervous system (Klotz et al, 2009). Interestingly, pioglitazone treatment alleviated the disease severity of EAE with selective inhibition of RORγt and Th17, but not Th1, differentiation.…”

Section: Ppars In T Cells and Autoimmunitymentioning

confidence: 99%

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Choi¹,

Bothwell

2012

Molecules and Cells

149

111

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Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARγ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4 + T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.

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“…As a consequence of the important roles, PPARs play in controlling metabolic homeostasis and inflammatory processes, they are often the therapeutic molecular targets for metabolic diseases such as diabetes (Chinetti et al 2000) and in the treatment of inflammatory disorders (Napimoga et al 2008, Hassumi et al 2009, Klotz et al 2009, Park et al 2009). In the present paper, we have investigated the effects of the 15d-PGJ 2 , an agonist of PPAR-γ, on disease outcome and immune function in T. cruzi-infected C57BL/6 mice.…”

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confidence: 99%

15d-PGJ2 modulates acute immune responses to Trypanosoma cruzi infection

Rodrigues

Miguel

Chica

et al. 2010

Mem. Inst. Oswaldo Cruz

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The acute phase of Trypanosoma cruzi infection is associated with a strong inflammatory reaction in the heart characterised by a massive infiltration of immune cells that is dependent on the T. cruzi strain and the host response. 15d-PGJ2 belongs to a new class of anti-inflammatory compounds with possible clinical applications. We evaluated the effects of 15d-PGJ2 administered during the acute phase of T. cruzi infection in mice. Mice were infected with the Colombian strain of T. cruzi and subsequently treated with 15d-PGJ2 repeatedly for seven days. The inflammatory infiltrate was examined by histologic analysis. Slides were immunohistochemically stained to count the number and the relative size of parasite nests. Infection-induced changes in serum cytokine levels were measured by ELISA. The results demonstrated that treatment with 15d-PGJ2 reduced the inflammatory infiltrate in the skeletal muscle at the site of infection and decreased the number of lymphocytes and neutrophils in the blood. In addition, we found that 15d-PGJ2 led to a decrease in the relative volume density of amastigote nests in cardiac muscle. T. cruzi-infected animals treated with 15d-PGJ2 displayed a statistically significant increase in IL-10 levels with no change in IFN-γ levels. Taken together, we demonstrate that treatment with 15d-PGJ2 in the acute phase of Chagas disease led to a controlled immune response with decreased numbers of amastigote nests, as measured by the volume density

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The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity

Cited by 294 publications

References 41 publications

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

15d-PGJ2 modulates acute immune responses to Trypanosoma cruzi infection

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