Activation of Aryl Hydrocarbon Receptor by Tcdd Prevents Diabetes in Nod Mice and Increases Foxp3 + T Cells in Pancreatic Lymph Nodes

• Published in: Immunotherapy Vol. 1; no. 4; pp. 539 - 547
• Main Authors: Kerkvliet, Nancy I, Steppan, Linda B, Vorachek, William, Oda, Shannon, Farrer, David, Wong, Carmen P, Pham, Duy, Mourich, Dan V
• Format: Journal Article
• Language: English
• Published: England Future Medicine Ltd 01.07.2009
• Subjects: Animals; CD4 Antigens - biosynthesis; Cell Proliferation - drug effects; Cells, Cultured; Diabetes; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Disease; Forkhead Transcription Factors - biosynthesis; Gene expression; Health sciences; Human subjects; Interleukin-2 Receptor alpha Subunit - biosynthesis; Laboratory animals; Ligands; Lymph Nodes - drug effects; Lymph Nodes - pathology; Metabolites; Mice; Mice, Inbred NOD; Pancreas; Pancreas - drug effects; Pancreas - pathology; Polychlorinated Dibenzodioxins - administration & dosage; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - immunology; Receptors, Aryl Hydrocarbon - metabolism; Rodents; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Type 1 diabetes; TCDD; AHR; regulatory T cell; NOD mice; 2,3,7,8-tetrachlorodibenzo-p-dioxin; aryl hydrocarbon receptor
• ISSN: 1750-743X; 1750-7448
• DOI: 10.2217/imt.09.24

The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR), is a novel inducer of adaptive Tregs. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most potent AHR ligand, induces adaptive CD4+CD25+ Tregs during an acute graft-versus-host (GvH) response and prevents the generation of allospecific cytotoxic T lymphocytes. TCDD also suppresses the induction of experimental autoimmune encephalitis in association with an expanded population of Foxp3+ Tregs. In this study, we show that chronic treatment of NOD mice with TCDD potently suppresses the development of autoimmune Type 1 diabetes in parallel with greatly reduced pancreatic islet insulitis and an expanded population of CD4+CD25+Foxp3+ cells in the pancreatic lymph nodes. When treatment with TCDD was terminated after 15 weeks (23 weeks of age), mice developed diabetes over the next 8 weeks in association with lower numbers of Tregs and decreased activation of AHR. Analysis of the expression levels of several genes associated with inflammation, T-cell activation and/or Treg function in pancreatic lymph node cells failed to reveal any differences associated with TCDD treatment. Taken together, the data suggest that AHR activation by TCDD-like ligands may represent a novel avenue for treatment of immune-mediated diseases.