Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes.
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.
Kerkvliet
Nancy I
NI
Oregon State University, Department of Microbiology, Corvallis, OR 97331, USA.
Steppan
Linda B
LB
Vorachek
William
W
Oda
Shannon
S
Farrer
David
D
Wong
Carmen P
CP
Pham
Duy
D
Mourich
Dan V
DV
D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008024:Ligands; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon