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Archives of Toxicology

, Volume 93, Issue 2, pp 355–368 | Cite as

Targeted deletion of the aryl hydrocarbon receptor in dendritic cells prevents thymic atrophy in response to dioxin

  • Celine A. Beamer
  • Joanna M. Kreitinger
  • Shelby L. Cole
  • David M. ShepherdEmail author
Immunotoxicology
First Online:
  • 147 Downloads

Abstract

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.

Keywords

Involution TCDD ITE I3C AhRd Apoptosis 
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Notes

Acknowledgements

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.

Author contributions

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.

Funding

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2018_2366_MOESM1_ESM.pdf (42 kb)
Supplementary material 1 Supplemental Table 1. Mouse strains examined in this study. (PDF 41 KB)
204_2018_2366_MOESM2_ESM.pdf (54 kb)
Supplementary material 2 Supplemental Figure 1. AhRdmice are unresponsive to TCDD-induced thymic atrophy at 10 µg/kg. Naïve wild-type mice (C57Bl/6) and mice expressing the low affinity receptor (AhRd mice) were gavaged with vehicle (anisole/peanut oil) or TCDD (10 or 100 µg/kg). Three indicators of toxicity: body weight (data not shown), thymus weight (A), and thymus cell number (B) were measured on day 7 to evaluate toxicity and thymic atrophy after low dose (10 µg/kg) and high dose (100 µg/kg) of TCDD. Data represents one of two independent experiments, n=8-12 per treatment group, mean + SEM; 2-way ANOVA, *p < 0.05 vehicle (PDF 53 KB)
204_2018_2366_MOESM3_ESM.pdf (4.9 mb)
Supplementary material 3 Supplemental Figure 2. Comparison of CD4/CD8 thymocyte subsets from vehicle and TCDD-exposed mice. C57Bl/6 and AhRd mice were gavaged with vehicle (anisole/peanut oil) or TCDD (10 or 100 µg/kg). Representative contour plots gating on live thymocytes from wild-type C57Bl/6 mice revealed a significant decline in the frequency of CD4+CD8+ DP thymocytes, as well as a relative enrichment in the percent of CD4-CD8- DN and CD4+CD8- and CD4-CD8+ SP thymocytes in 10 µg/kg TCDD-treated mice compared to vehicle control on day 7. These shifts in CD4/CD8 thymocyte subsets were not observed in AhRd mice treated with 10 µg/kg TCDD but were observed following administration of 100 µg/kg TCDD. The mean percentages of the CD4/CD8 thymocyte subsets + SEM are indicated in the plots. Data represents one of two independent experiments, n=8-12 per treatment group; 2-way ANOVA, *p < 0.05 vehicle (PDF 5042 KB)
204_2018_2366_MOESM4_ESM.pdf (178 kb)
Supplementary material 4 Supplemental Figure 3. CD4/CD8 thymocyte subsets from CD11cCreAhRfxand CD11c-AhRfxmice exposed to vehicle or TCDD. AhR conditional knockout and CD11c-AhRfx control mice were exposed to either solvent/peanut oil vehicle or 100 µg/kg TCDD. Representative contour plots gating on live thymocytes revealed a significant decline in the frequency of CD4+CD8+ DP thymocytes, as well as a relative enrichment in the percent of CD4-CD8- DN and CD4+CD8- and CD4-CD8+ SP thymocytes in CD11c-AhRfx mice exposed to 100 µg/kg TCDD compared to vehicle controls on day 7. These shifts in CD4/CD8 thymocyte subsets were not observed in CD11cCreAhRfx mice treated with 100 µg/kg TCDD. The mean percentages of the CD4/CD8 thymocyte subsets + SEM are indicated in the plots. Data represents one of two independent experiments, n=3-4 per treatment group; 2-way ANOVA, *p < 0.05 vehicle (PDF 177 KB)

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Authors and Affiliations

  1. 1.Department of Biomedical and Pharmaceutical SciencesUniversity of MontanaMissoulaUSA
  2. 2.Division of Biological SciencesUniversity of MontanaMissoulaUSA

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