title: Activation of the Aryl Hydrocarbon Receptor by 10-Cl-BBQ Prevents Insulitis and Effector T Cell Development Independently of Foxp3+ Regulatory T Cells in Nonobese Diabetic Mice.
abstract: Aryl hydrocarbon receptor (AhR) activation by high-affinity ligands mediates immunosuppression in association with increased regulatory T cells (Tregs), making this transcription factor an attractive therapeutic target for autoimmune diseases. We recently discovered 10-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (10-Cl-BBQ), a nanomolar affinity AhR ligand with immunosuppressive activity and favorable pharmacologic properties. In this study, we tested the consequences of AhR activation in the NOD model. Oral 10-Cl-BBQ treatment prevented islet infiltration without clinical toxicity, whereas AhR-deficient NOD mice were not protected. Suppression of insulitis was associated with an increased frequency, but not total number, of Foxp3(+) Tregs in the pancreas and pancreatic lymph nodes. The requirement for Foxp3(+) cells in AhR-induced suppression of insulitis was tested using NOD.Foxp3(DTR) mice, which show extensive islet infiltration upon treatment with diphtheria toxin. AhR activation prevented the development of insulitis caused by the depletion of Foxp3(+) cells, demonstrating that Foxp3(+) cells are not required for AhR-mediated suppression and furthermore that the AhR pathway is able to compensate for the absence of Foxp3(+) Tregs, countering current dogma. Concurrently, the development of disease-associated CD4(+)Nrp1(+)Foxp3(-)RORγt(+) cells was inhibited by AhR activation. Taken together, 10-Cl-BBQ is an effective, nontoxic AhR ligand for the intervention of immune-mediated diseases that functions independently of Foxp3(+) Tregs to suppress pathogenic T cell development.
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331; and.
authors.forename: Allison K
authors.initials: AK
authors.lastname: Ehrlich
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331; and.
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Pennington
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331; and.
authors.forename: Xisheng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331; and.
authors.forename: Diana
authors.identifier: http://orcid.org/0000-0002-3982-0327
authors.initials: D
authors.lastname: Rohlman
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331; and.
authors.forename: Sumit
authors.initials: S
authors.lastname: Punj
authors.affiliation: College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331.
authors.forename: Christiane V
authors.identifier: http://orcid.org/0000-0003-3787-5583
authors.initials: CV
authors.lastname: Löhr
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331; and.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Newman
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331; and.
authors.forename: Siva K
authors.initials: SK
authors.lastname: Kolluri
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331; and nancy.kerkvliet@oregonstate.edu.
authors.forename: Nancy I
authors.initials: NI
authors.lastname: Kerkvliet
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D007249:Inflammation / Q000517:prevention & control*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology; D007546:Isoquinolines / Q000008:administration & dosage* / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: C000593972:10-chloro-7H-benzimidazo(2,1-a)benzo(de)Isoquinolin-7-one; D001562:Benzimidazoles; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D007546:Isoquinolines; D018336:Receptors, Aryl Hydrocarbon