AHR Function in Lymphocytes: Emerging Concepts

The aryl hydrocarbon receptor (AHR) is an important regulator of the development and function of both innate and adaptive immune cells through roles associated with AHR's ability to respond to cellular and dietary ligands. Recent findings have revealed tissue and context-specific functions for AHR in both homeostasis and in during an immune response. I review these findings here, and integrate them into the current understanding of the mechanisms that regulate AHR transcription and function. I propose a conceptual framework in which AHR function is determined by three factors: the amount of AHR in any given cell, the abundance and potency of AHR ligands within certain tissues, and the tissue microenvironment wherein AHR+ cells reside. This complexity emphasizes the necessity cell-type specific genetic approaches towards the study of AHR function.

TrendsRegulated expression of AHR by immunological stimuli, such as cytokines, can determine its action in the corresponding cells, thus influencing host immunity.Tissues that are exposed to the external environmental stimuli, such as the gut and the skin, are the host milieu that is enriched in both AHR-expressing cells and in AHR ligands.Despite a myriad of genes that can be bound by AHR in different cell types (e.g., hepatocytes) upon treatment with pollutants such as dioxin, unique gene targets of AHR might be present, especially in physiological conditions, without its activation by xenobiotic compounds.AHR can also partner with other factors to exert its complex function in the immune system. The factors can have tissue and context-specific expression, thus presenting an additional regulatory level to AHR function.Identification and characterization of compounds that are either derived from food, generated endogenously by the host cells, or by indigenous microbes will facilitate drug discovery by presenting strategies towards targeting the AHR pathway in different tissues and disease settings.