title: T-bet over-expression regulates aryl hydrocarbon receptor-mediated T helper type 17 differentiation through an interferon (IFN)γ-independent pathway.
abstract: Various transcription factors are also known to enhance or suppress T helper type 17 (Th17) differentiation. We have shown previously that the development of collagen-induced arthritis was suppressed in T-bet transgenic (T-bet Tg) mice, and T-bet seemed to suppress Th17 differentiation through an interferon (IFN)-γ-independent pathway, although the precise mechanism remains to be clarified. The present study was designed to investigate further the mechanisms involved in the regulation of Th17 differentiation by T-bet over-expression, and we found the new relationship between T-bet and aryl hydrocarbon receptor (AHR). Both T-bet Tg mice and IFN-γ-/--over-expressing T-bet (T-bet Tg/IFN-γ-/-) mice showed inhibition of retinoic acid-related orphan receptor (ROR)γt expression and IL-17 production by CD4+T cells cultured under conditions that promote Th-17 differentiation, and decreased IL-6 receptor (IL-6R) expression and signal transducer and activator of transcription-3 (STAT-3) phosphorylation in CD4+T cells. The mRNA expression of ahr and rorc were suppressed in CD4+T cells cultured under Th-17 conditions from T-bet Tg mice and T-bet Tg/IFN-γ-/-mice. CD4+T cells of wild-type (WT) and IFN-γ-/-mice transduced with T-bet-expressing retrovirus also showed inhibition of IL-17 production, whereas T-bet transduction had no effect on IL-6R expression and STAT-3 phosphorylation. Interestingly, the mRNA expression of ahr and rorc were suppressed in CD4+T cells with T-bet transduction cultured under Th17 conditions. The enhancement of interleukin (IL)-17 production from CD4+T cells by the addition of AHR ligand with Th17 conditions was cancelled by T-bet over-expression. Our findings suggest that T-bet over-expression-induced suppression of Th17 differentiation is mediated through IFN-γ-independent AHR suppression.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yokosawa
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tahara
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Iizuka-Koga
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Segawa
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tsuboi
authors.affiliation: Division of Nephrology, Department of Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.|Department of Anatomy and Embryology, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yoh
authors.affiliation: Department of Anatomy and Embryology, University of Tsukuba, Tsukuba city, Ibaraki, Japan.|International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba city, Ibaraki, Japan.|Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba city, Ibaraki, Japan.|Laboratory Animal Resource Center (LARC), University of Tsukuba, Tsukuba city, Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Matsumoto
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sumida
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D056747:Immunomodulation; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D014161:Transduction, Genetic; D000098815:T-bet Transcription Factor
chemical_list: D015850:Interleukin-6; D018336:Receptors, Aryl Hydrocarbon; D050796:STAT3 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma
keywords: AHR; IL-17; T-bet over-expression