The aryl hydrocarbon receptor: a molecular pathway for the environmental control of the immune response

Abstract

Environmental factors have significant effects on the development of autoimmune diseases. The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) is controlled by endogenous and environmental small molecules. Hence, AHR provides a molecular pathway by which endogenous and environmental signals can influence the immune response and the development of autoimmune diseases. AHR also provides a target for therapeutic intervention in immune-mediated disorders. In this review, we discuss the role of AHR in the regulation of T-cell differentiation and autoimmunity.

Figure 1

Role of aryl hydrocarbnon receptor (AHR) signalling on CD4⁺ T cells. AHR signaling in FoxP3⁺ regulatory T (Treg) cells triggers the demethylation of Foxp3 and transactivates its promoter. AHR signalling also interferes with the activation of signal transducer and activator of transcription 1 (STAT‐1), which mediates the inhibitory effects of interferon‐γ (IFN‐γ) on Foxp3⁺ Treg cells. Finally, AHR activation up‐regulates the expression of CD39 and of Aiolos, which then inhibits interleukin‐2 (IL‐2) production. AHR signalling in IL‐10⁺ type 1 regulatory (Tr1) cells triggers the expression of IL‐10 and the Tr1 autocrine growth factor IL‐21. In addition, AHR activation also up‐regulates granzyme B expression. AHR signalling in T helper type 17 (Th17) cells promotes the expression of IL‐21 and IL‐22, and it also limits the activation of STAT‐1 and STAT‐5, which mediate the inhibitory effects of IFNγ and IL‐2 on Th17 cell differentiation, respectively. Finally, AHR activation inhibits the production of IL‐2 through a mechanism dependent on Aiolos.