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-1α. 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/Δ 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/Δ mice were resistant to TCDD treatment in vivo. In contrast, benzo(a)pyrene, another AHR ligand, still caused thymic involution in Lck-Cre;Arntflox/Δ mice. Finally, fetal thymus organ culture using Lck-Cre;Arntflox/Δ and K5-Cre;Arntflox/Δ (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.