Peroxisome Proliferator-Activated Receptor α and γ Agonists Together with TGF-β Convert Human CD4+CD25− T Cells into Functional Foxp3+ Regulatory T Cells

Jin, Lei; Hasegawa, Hitoshi; Matsumoto, Takuya; Yasukawa, Masaki

doi:10.4049/jimmunol.1001437

Cited by 72 publications

(66 citation statements)

References 83 publications

(125 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In human T cells, PPAR-a agonists bezafibrate and GW7647 can stabilize Foxp3 expression through epigenetic modification of the Foxp3 promoter. 66 Therefore, PPAR-a is likely critical for maintaining the suppressive functions of both murine and human Tregs in vitro. 66,67 The molecular mechanism behind PPAR-a-and PPAR-b/d-dependent Th17/Treg development remains to be elucidated, although one possible mechanism involves the interaction among PPAR subtypes.…”

Section: 58mentioning

confidence: 99%

The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases

Park

Fan

2015

Cell Mol Immunol

View full text Add to dashboard Cite

Nuclear receptors in the cell play essential roles in environmental sensing, differentiation, development, homeostasis, and metabolism and are thus highly conserved across multiple species. The anti-inflammatory role of nuclear receptors in immune cells has recently gained recognition. Nuclear receptors play critical roles in both myeloid and lymphoid cells, particularly in helper CD41 T-cell type 17 (Th17) and regulatory T cells (Treg). Th17 and Treg are closely related cell fates that are determined by orchestrated cytokine signaling. Recent studies have emphasized the interactions between nuclear receptors and the known cytokine signals and how such interaction affects Th17/Treg development and function. This review will focus on the most recent discoveries concerning the roles of nuclear receptors in the context of therapeutic applications in autoimmune diseases.

show abstract

Section: 58mentioning

confidence: 99%

The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases

Park

Fan

2015

Cell Mol Immunol

View full text Add to dashboard Cite

show abstract

“…PPARd agonists also ameliorate EAE by inhibiting both Th1 and Th17 differentiation (28,29). In contrast, the effects of PPAR on iTreg differentiation are controversial (30)(31)(32). PPAR-mediated stimulation appears to enhance nTreg differentiation, but not iTreg differentiation, in mice (30,31,33).…”

Section: Ra Enhances Foxp3mentioning

confidence: 99%

“…PPAR-mediated stimulation appears to enhance nTreg differentiation, but not iTreg differentiation, in mice (30,31,33). However, in humans, PPAR may directly or indirectly enhance iTreg differentiation (32). It was reported that PPARg stimulation induces RALDH2 expression in human DCs (34), but not significantly in murine DC (5), suggesting the possible involvement of RA in the PPARg agonist-treated human DCs to enhance iTreg differentiation.…”

Section: Ra Enhances Foxp3mentioning

confidence: 99%

Retinoid X Receptor Agonists Modulate Foxp3+ Regulatory T Cell and Th17 Cell Differentiation with Differential Dependence on Retinoic Acid Receptor Activation

Takeuchi

Yokota-Nakatsuma

Ohoka

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Retinoic acid (RA) enhances TGF-β–dependent differentiation of Foxp3+ inducible regulatory T cells (iTregs) and inhibits Th17 differentiation by binding to the RA receptor (RAR)/retinoid X receptor (RXR) heterodimer. The major physiologic RA, all-trans-RA, binds to RAR but not to RXR at physiological concentrations. It remained unclear whether RXR-mediated stimulation affected the iTregs and Th17 differentiation. We found in this study that the RXR agonists, PA024 and tributyltin, augmented the ability of all-trans-RA or the RAR agonist Am80 to enhance CD4+CD25− T cells to acquire Foxp3 expression and suppressive function. However, they failed to enhance Foxp3 expression in the presence of the RAR antagonist LE540, suggesting that the effect depends on RAR-mediated signals. They exerted the effect largely by augmenting the ability of all-trans-RA to suppress the production of IL-4, IL-21, and IFN-γ that inhibited Foxp3 expression. Agonists of peroxisome proliferator-activated receptors and liver X receptors (LXRs), permissive partners of RXR, failed to enhance Foxp3 expression. In contrast, RXR agonists and LXR agonists suppressed IL-17 expression. The RXR-mediated suppression was not canceled by blocking RAR stimulation but was likely to involve permissive activation of LXRs. All-trans-RA and an agonist of RXR or LXR additively suppressed IL-17 expression when the all-trans-RA concentration was low. RXR agonists also suppressed Ccr6 expression that is essential for Th17 cells to enter the CNS. Accordingly, tributyltin treatment of mice ameliorated experimental autoimmune encephalomyelitis through regulating Th17 cell activities. These results suggest that RXR stimulation modulates Foxp3+ iTreg and Th17 differentiation with differential dependence on RAR-mediated stimulation.

show abstract

“…DC cell surface expression and the expression of Foxp3 and IL-10 in CD4 + T cells were analyzed using each of the mAbs described in the Abs and reagents section labeled with FITC or PE on a FACSCalibur flow cytometer (BD Biosciences), as described previously (51). For intracellular Foxp3 and IL-10 staining, permeabilization was performed in accordance with the manufacturer's protocol.…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

“…In vitro T regulatory activity was modified as described previously (51) and as reported by Gonzalez-Rey et al (30). Human Th1 cells were generated from naive CD4 + CD45RA + T cells.…”

Section: In Vitro T Regulatory Activitymentioning

confidence: 99%

Protein Kinase C Inhibitor Generates Stable Human Tolerogenic Dendritic Cells

Matsumoto

Hasegawa

Onishi

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Tolerogenic dendritic cells (DCs) are a promising tool for a specific form of cellular therapy whereby immunological tolerance can be induced in the context of transplantation and autoimmunity. From libraries of bioactive lipids, nuclear receptor ligands, and kinase inhibitors, we screened conventional protein kinase C inhibitors (PKCIs) bisindolylmaleimide I, Gö6983, and Ro32-0432 with strong tolerogenic potential. PKCI-treated human DCs were generated by subjecting them to a maturation process after differentiation of immature DCs. The PKCI-treated DCs had a semimature phenotype, showing high production of IL-10, and efficiently induced IL-10–producing T cells and functional Foxp3+ regulatory T cells from naive CD4+ T cells, thus eliciting a strong immunosuppressive function. They also showed CCR7 expression and sufficient capacity for migration toward CCR7 ligands. Additionally, PKCI-treated DCs were highly stable when exposed to inflammatory stimuli such as proinflammatory cytokines or LPS. Conventional PKCIs inhibited NF-κB activation of both the canonical and noncanonical pathways of DC maturation, thus suppressing the expression of costimulatory molecules and IL-12 production. High production of IL-10 in PKCI-treated DCs was due to not only an increase of intracellular cAMP, but also a synergistic effect of increased cAMP and NF-κB inhibition. Moreover, PKCI-treated mouse DCs that had properties similar to PKCI-treated human DCs prevented graft-versus-host disease in a murine model of acute graft-versus-host disease. Conventional PKCI-treated DCs may be useful for tolerance-inducing therapy, as they satisfy the required functional characteristics for clinical-grade tolerogenic DCs.

show abstract

Peroxisome Proliferator-Activated Receptor α and γ Agonists Together with TGF-β Convert Human CD4+CD25− T Cells into Functional Foxp3+ Regulatory T Cells

Abstract: Material

Cited by 72 publications

References 83 publications

The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases

The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases

Retinoid X Receptor Agonists Modulate Foxp3+ Regulatory T Cell and Th17 Cell Differentiation with Differential Dependence on Retinoic Acid Receptor Activation

Protein Kinase C Inhibitor Generates Stable Human Tolerogenic Dendritic Cells

Contact Info

Product

Resources

About