title: T cell-specific disruption of arylhydrocarbon receptor nuclear translocator (Arnt) gene causes resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced thymic involution.
abstract: The arylhydrocarbon receptor nuclear translocator (ARNT) is a member of the basic helix-loop-helix, PER-ARNT-SIM family of heterodimeric transcription factors, and serves as a dimerization partner for arylhydrocarbon receptor (AHR) and hypoxia-inducible factor-1alpha. To assess the function of ARNT in T cells, we disrupted the Arnt gene specifically in T cells of mice by conditional gene targeting using T cell-specific p56(lck)-Cre (Lck-Cre) transgenic Arnt-floxed mice. Thus generated, T cell-specific Arnt-disrupted mice (Lck-Cre;Arnt(flox/Delta) transgenic mice) exhibited complete loss of the expression of ARNT protein only in T cells, and were viable and appeared normal. The Arnt-disrupted T cells in the thymus were phenotypically and histologically normal. The Arnt-deficient T cells in the spleen were capable of responding to TCR stimulation in vitro. However, unlike normal mice in which exposure to the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an AHR ligand, resulted in thymic involution, the thymus of Lck-Cre;Arnt(flox/Delta) mice were resistant to TCDD treatment in vivo. In contrast, benzo(a)pyrene, another AHR ligand, still caused thymic involution in Lck-Cre;Arnt(flox/Delta) mice. Finally, fetal thymus organ culture using Lck-Cre;Arnt(flox/Delta) and K5-Cre;Arnt(flox/Delta) (epithelial cell-specific Arnt-disrupted mice) showed that thymocytes rather than thymic epithelial cells are predominantly responsible for TCDD-induced thymic atrophy. Our results indicate that ARNT in T lineage cells is essential for TCDD-mediated thymic involution.
authors.affiliation: Department of Biochemistry, Kagawa Medical University, Kagawa, Japan. tomita@genome.tokushima-u.ac.jp
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tomita
authors.forename: Hou-Bo
authors.initials: HB
authors.lastname: Jiang
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ueno
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takagi
authors.forename: Keiko
authors.initials: K
authors.lastname: Tohi
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Maekawa
authors.forename: Akira
authors.initials: A
authors.lastname: Miyatake
authors.forename: Aizo
authors.initials: A
authors.lastname: Furukawa
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Junji
authors.initials: J
authors.lastname: Takeda
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Takahama
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001284:Atrophy / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D018390:Gene Targeting; D007113:Immunity, Innate / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
chemical_list: C497397:Arnt protein, mouse; D004268:DNA-Binding Proteins; D000072317:Polychlorinated Dibenzodioxins; D011948:Receptors, Antigen, T-Cell; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator