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

• Published in: Archives of toxicology Vol. 93; no. 2; pp. 355 - 368
• Main Authors: Beamer, Celine A., Kreitinger, Joanna M., Cole, Shelby L., Shepherd, David M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-02-2019; Springer Nature B.V
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Aromatic compounds; Atrophy; Atrophy - chemically induced; Atrophy - genetics; Atrophy - prevention & control; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biomedical and Life Sciences; Biomedicine; CD11c antigen; CD4 antigen; CD8 antigen; Cell activation; Clonal deletion; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - pathology; Dendritic structure; Differentiation; Dioxins; Dose-Response Relationship, Drug; Emigration; Environmental Health; Fas Ligand Protein - metabolism; fas Receptor - metabolism; FasL protein; Female; Gene deletion; Hydrocarbons; Immunotoxicology; Indoles; Indoles - administration & dosage; Indoles - pharmacology; Indoles - toxicity; Lymphocytes T; Male; Mice, Inbred C57BL; Mice, Knockout; Molecular modelling; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Pollutants; Polychlorinated Dibenzodioxins - toxicity; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; TCDD; Thiazoles - administration & dosage; Thiazoles - toxicity; Thymocytes; Thymus; Thymus Gland - drug effects; Thymus Gland - pathology; TCDD; I3C; Involution; AhR; ITE; Apoptosis; AhRd
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-018-2366-x

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-(1
H
-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.