Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis.

In autoimmune hepatitis (AIH) imbalance between Treg and Th17-cells has been linked to low levels of CD39, an ectoenzyme that hydrolyses ATP ultimately generating immunosuppressive adenosine. Upregulation of CD39 results from activation of aryl-hydrocarbon-receptor (AHR), which mediates toxin responses to modulate T-cell immunity. Upon binding to exogenous or endogenous ligands, AHR dimerizes with the aryl-hydrocarbon-receptor-nuclear-translocator (ARNT) or other 'non-canonical' binding factors like oestrogen-receptor-α (Erα) to modulate gene transcription. The AHR/ARNT complex is in turn regulated by hypoxia-inducible-factor-1α (HIF-1α) and the aryl-hydrocarbon receptor-repressor (AHRR). In this study we investigated whether altered AHR signalling underlies defective CD39 expression and function in AIH Treg and Th17-cells, therefore contributing to regulatory/effector cell imbalance.Treg and Th17-cells, obtained from the peripheral blood of 49 AIH patients and 21 healthy subjects (HS), were tested for response to AHR endogenous and exogenous ligands.When compared to HS, AIH Treg and Th17-cells displayed impaired response to AHR activation, as reflected by impaired upregulation of CD39, delayed increase in ectoenzymatic activity and defective Treg suppressive function. These impairments resulted, at least in part, from heightened levels of AHRR and Erα in Treg and high HIF-1α in Th17-cells and were reverted upon molecular blockade. Importantly, in AIH Treg, the binding affinity of AHR was higher for Erα than ARNT.In AIH, high levels of AHRR and HIF-1α inhibit AHR signalling in Treg and Th17-cells. AHR non-canonical binding to Erα further amplifies lack of effective CD39 upregulation. Blockade of these inhibitory and/or non-canonical activation pathways represents a potential therapeutic approach to restore CD39 and immunohomeostasis in AIH.

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