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* Department of Biochemistry, Kagawa Medical University, Kagawa, Japan;
Department of Immune System Development, The Institute of Physical and Chemical Research, Research Center for Allergy and Immunology and
Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima, Japan; Departments of
Plastic Surgery and
¶ Social Environmental Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; and
|| Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
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-1
. 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 p56lck-Cre (Lck-Cre) transgenic Arnt-floxed mice. Thus generated, T cell-specific Arnt-disrupted mice (Lck-Cre;Arntflox/
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;Arntflox/ mice were resistant to TCDD treatment in vivo. In contrast, benzo(a)pyrene, another AHR ligand, still caused thymic involution in Lck-Cre;Arntflox/ mice. Finally, fetal thymus organ culture using Lck-Cre;Arntflox/ and K5-Cre;Arntflox/ (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.
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