TitleActivation 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.
Publication TypeJournal Article
Year of Publication2016
AuthorsEhrlich, AK, Pennington, JM, Wang, X, Rohlman, D, Punj, S, Löhr, CV, Newman, MT, Kolluri, S, Kerkvliet, NI
JournalJ Immunol
Volume196
Issue1
Pagination264-73
Date Published2016 Jan 01
ISSN1550-6606
KeywordsAnimals, Benzimidazoles, Diabetes Mellitus, Type 1, Enzyme Activation, Forkhead Transcription Factors, Immunosuppressive Agents, Inflammation, Islets of Langerhans, Isoquinolines, Lymph Nodes, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Receptors, Aryl Hydrocarbon, Th1 Cells, Th17 Cells
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.

DOI10.4049/jimmunol.1501789
Alternate JournalJ. Immunol.
PubMed ID26573835
PubMed Central IDPMC4684970
Grant ListR01 ES016651 / ES / NIEHS NIH HHS / United States
5R01ES016651 / ES / NIEHS NIH HHS / United States
5T32ES007060-35 / ES / NIEHS NIH HHS / United States
P01 ES000040 / ES / NIEHS NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States