Abstract
The aryl hydrocarbon receptor (AhR) has been attributed with anti-inflammatory effects in the development of pathological immune responses leading to experimental autoimmune encephalomyelitis (EAE) via the induction of regulatory T cells. In agreement with previously published findings, we find that TCDD administration confers protection from EAE, however, this immuno-modulatory effect was not the consequence of de novo Treg generation, but the inhibition of Th17 cell differentiation. Systemic application of FICZ at the time of immunization also reduced EAE pathology albeit to a lesser degree than TCDD. In vitro Th17 differentiation in the presence of AhR agonists, including TCDD, promoted IL-17 and IL-22 expression, but did not induce Treg differentiation. AhR affinity influenced the amounts of IL-17 and IL-22 protein that was secreted by Th17 cells, but did not seem to affect susceptibility to EAE in vivo. Making use of conditional AhR-deficient mice, we show that the anti-inflammatory effect of TCDD depends on AhR activation in both T cells and dendritic cells, further emphasising the ability of TCDD to interfere with T effector cell differentiation in vivo. The dichotomy between the in vivo and in vitro effects of AhR reveals the complexity of the AhR pathway, which has the capacity of affecting different AhR-expressing cell types involved in mounting immune responses, thus participating in defining their outcome.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / deficiency
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Basic Helix-Loop-Helix Transcription Factors / immunology
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Carbazoles / pharmacology
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Cell Differentiation / drug effects
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Cells, Cultured
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Dendritic Cells / drug effects
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Dendritic Cells / immunology
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Dendritic Cells / pathology
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Encephalomyelitis, Autoimmune, Experimental / chemically induced
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Environmental Pollutants / pharmacology
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Gene Expression Regulation
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Immunity, Cellular / drug effects*
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Immunologic Factors / pharmacology
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Interleukin-17 / genetics
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Interleukin-17 / immunology*
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Interleukin-22
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Interleukins / genetics
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Interleukins / immunology
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Lymphocyte Activation / drug effects
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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Polychlorinated Dibenzodioxins / analogs & derivatives
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Polychlorinated Dibenzodioxins / pharmacology
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Receptors, Aryl Hydrocarbon / deficiency
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Receptors, Aryl Hydrocarbon / genetics*
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Receptors, Aryl Hydrocarbon / immunology
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Signal Transduction
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / pathology
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Th17 Cells / drug effects
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Th17 Cells / immunology*
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Th17 Cells / pathology
Substances
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6-formylindolo(3,2-b)carbazole
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Ahr protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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Carbazoles
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Environmental Pollutants
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Immunologic Factors
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Interleukin-17
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Interleukins
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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Polychlorinated Dibenzodioxins
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Receptors, Aryl Hydrocarbon
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myelin oligodendrocyte glycoprotein (35-55)
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1,2,7,8-tetrachlorodibenzo-p-dioxin
Grants and funding
This study is funded by an ERC Advanced Grant (No.232782) to B.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript