Targeted deletion of the aryl hydrocarbon receptor in dendritic cells prevents thymic atrophy in response to dioxin
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In nearly every species examined, administration of the persistent environmental pollutant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD) causes profound immune suppression and thymic atrophy in an aryl hydrocarbon receptor (AhR) dependent manner. Moreover, TCDD alters the development and differentiation of thymocytes, resulting in decreases in the relative proportion and absolute number of double positive (DP, CD4+CD8+) thymocytes, as well as a relative enrichment in the relative proportion and absolute number of double negative (DN, CD4−CD8−) and single-positive (SP) CD4+CD8− and CD4−CD8+ thymocytes. Previous studies suggested that the target for TCDD-induced thymic atrophy resides within the hemopoietic compartment and implicated apoptosis, proliferation arrest of thymic progenitors, and emigration of DN thymocytes to the periphery as potential contributors to TCDD-induced thymic atrophy. However, the precise cellular and molecular mechanisms involved remain largely unknown. Our results show that administration of 10 µg/kg TCDD and 8 mg/kg 2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester (ITE) induced AhR-dependent thymic atrophy in mice on day 7, whereas 100 mg/kg indole 3-carbinol (I3C) did not. Though our studies demonstrate that TCDD triggers a twofold increase in the frequency of apoptotic thymocytes, TCDD-induced thymic atrophy is not dependent on Fas–FasL interactions, and thus, enhanced apoptosis is unlikely to be a major mechanistic contributor. Finally, our results show that activation of the AhR in CD11c+ dendritic cells is directly responsible for TCDD-induced alterations in the development and differentiation of thymocytes, which results in thymic atrophy. Collectively, these results suggest that CD11c+ dendritic cells play a critical role in mediating TCDD-induced thymic atrophy and disruption of T lymphocyte development and differentiation in the thymus.
KeywordsInvolution TCDD ITE I3C AhRd Apoptosis
The authors wish to thank the following scientists: Pam Shaw (Fluorescence Cytometry Core) and Britten Postma (Animal Core) for the shared expertise needed to conduct and/or analyze the experiments described in this manuscript.
CAB, JMK, and DMS designed the studies, coordinated the experiments, prepared the figures, and composed the manuscript. SLC performed the qRT-PCR analysis and assisted with experimental harvests. All authors have read and approved the final version of the manuscript.
Research reported in this publication was supported by the National Institute of Environmental Health Sciences and the National Institute of General Medical Sciences of the National Institutes of Health under Grant numbers R01-ES013784 (DMS), P30-GM103338, P20-GM103546. JMK was supported by the American Association of Immunologists through Careers in Immunology Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Conflict of interest
The authors declare that they have no conflict of interest.
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