Role of the aryl hydrocarbon receptor in establishing oral tolerance

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In this project the role of the aryl hydrocarbon receptor in oral tolerance will be analysed in mouse models. Oral tolerance is a vital function of the immune system, ensuring that no immune response is raised against harmless food proteins. Our previous work has demonstrated that feeding mice with the man-made environmental pollutant 2,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD) destabilizes oral tolerance. TCDD is a strong activator of the intracellular transcription factor aryl hydrocarbon receptor (AhR). Underlying causes of TCDD-impaired oral tolerance were changes in the cytokine secretion of gut draining dendritic cells, correlated to changes in the balance of regulatory T cells and inflammatory T cells. For mice, which lack the AhR , i.e. the sensor for substances like TCDD, oral tolerance was also impaired, albeit mechanisms differed. In AhR-deficient mice gut lymphocytes involved in regulatory functions were significantly reduced. Many edible plants contain compounds, which bind and activate the AhR similar to TCDD. However, it is unknown whether such compounds, e.g. indoles or polyphenols, affect or impair oral tolerance. Many plant-derived potential AhR ligands, such as indol-3-carbinol, quercetin oder epigallo-catechingallate are marketed as nutritional complements. We want to analyse whether also plant-derived AhR-ligands affect oral tolerance, and whether this influences food allergies. In a second part the underlying mechanisms of AhR-dependent disturbances of oral tolerance shall be dissected using conditional AhR-deficient mouse models. Thereby we want to identify the cells and potential factors such as cytokines, which are involved. We expect our data to contribute to a better understanding of the role of AhR in the gut immune system. Moreover, the data will be prerequisite for any therapeutic or preventive use of AhR-ligands in oral tolerance or food allergy.