Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes

Immunotherapy. 2009 Jul;1(4):539-47. 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.

Keywords: 2,3,7,8-tetrachlorodibenzo-p-dioxin; AHR; NOD mice; TCDD; Type 1 diabetes; aryl hydrocarbon receptor; regulatory T cell.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4 Antigens / biosynthesis
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Forkhead Transcription Factors / biosynthesis
  • Interleukin-2 Receptor alpha Subunit / biosynthesis
  • Ligands
  • Lymph Nodes / drug effects
  • Lymph Nodes / pathology*
  • Mice
  • Mice, Inbred NOD
  • Pancreas / drug effects
  • Pancreas / pathology
  • Polychlorinated Dibenzodioxins / administration & dosage*
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / immunology
  • Receptors, Aryl Hydrocarbon / metabolism*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / pathology


  • CD4 Antigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Ligands
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon