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

AhR activation by high affinity ligands mediates immunosuppression in association with increased regulatory T cells, 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. Here, we tested the consequences of AhR activation in the NOD model. Oral 10-Cl-BBQ treatment prevented islet infiltration without clinical toxicity, while 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.Foxp3DTR 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 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, non-toxic AhR ligand for the intervention of immune-mediated diseases that functions independently of Foxp3+ Tregs to suppress pathogenic T cell development.

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

“…1). Moreover, there is increasing evidence that the AhR plays a prominent role in physiology and pathophysiology including important roles in the immune function, autoimmunity, gastrointestinal function, inflammation and cancer (Benson and Shepherd 2011; Boitano et al 2010; Ehrlich et al 2016; Esser 2012; Kerkvliet et al 2009; Marshall and Kerkvliet 2010; Murray et al 2010; Punj et al 2014; Quintana et al 2008; Veldhoen et al 2008) and development of selective AhR modulators is a promising new area of pharmacological research, particularly for cancer chemotherapy (Murray et al 2014; Safe et al 2013). …”

AhR activation increases IL‐2 production by alloreactive CD4+ T cells initiating the differentiation of mucosal‐homing Tim3+Lag3+ Tr1 cells

“…CD4 + T cells are particularly sensitive targets for AhR regulation, and activation of AhR by exogenous ligands results in suppression of Th1‐, Th2‐ and Th17‐dependent immunity . Accordingly, treatment of mice with AhR ligands has been shown to ameliorate the development of several T‐cell dependent autoimmune diseases, such as type 1 diabetes , inflammatory bowel disease , and experimental autoimmune encephalomyelitis , as well as to suppress transplant rejection and inhibit graft‐versus‐host (GVH) disease . The potent efficacy of AhR ligands in these preclinical models supports the development of AhR ligands for therapeutic use in prevention and treatment of immune‐mediated diseases .…”

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

“…With the use of TCDD ( 3 ) it has been reported that upregulation of AhR resulted in downregulation of immune responses . More recent work demonstrates that activation of the AhR pathway results in the increased frequency of regulatory T cells (Tregs) that lead to immune tolerance . Preliminary reports suggest that TNBC and ER‐negative patients with higher densities of Tregs experienced significantly longer overall and disease‐free survival, than those with lower Treg levels …”

“…10‐Cl‐BBQ showed high AhR affinity and promoted cytosol to nuclear translocation of the AhR at nanomolar concentrations. Importantly 33 with a short serum half‐life (2 hours) and no acute toxicity at therapeutic doses, was found to induce Tregs in vivo, leading to the possibility of the AhR to be targeted for immune‐mediated diseases …”