Role of the aryl hydrocarbon receptor nuclear translocator in establishing lymphocyte and innate lymphoid cells of the intestinal tract and the skin

Abstract Background The aryl hydrocarbon receptor (AHR) is a transcription factor that controls development of innate and adaptive lymphoid cells in the intestinal mucosa and skin. Pharmacological ligands for AHR include dioxins, whereas physiological ligands include tryptophan metabolites from nutritional components or tryptophan catabolites produced by microbiota. AHR is thus an important link between environmental stimuli and immunity at barrier organs. One binding partner for AHR is the aryl hydrocarbon nuclear translocator (ARNT). A key question is whether the immune functions of AHR are solely mediated by AHR–ARNT complexes. We aimed to assess the importance of ARNT for lymphocyte populations of the intestine and the skin. Methods Mice expressing a Vav-Cre transgene were backcrossed to mice with floxed Arnt alleles to produce Vav-Cre Arnt fl/fl mice that have deleted ARNT in all haemopoietic cells. The effect of ARNT loss for lymphocytes in the skin and in the small intestine was analysed by flow cytometry and confocal microscopy. Findings Vav-Cre Arnt fl/fl mice had a three-fold reduction of TCRαβCD8αα+ and four-fold reduction of TCRγδ+ cells in the intraepithelial layer of the small intestine compared with wild type controls. They also lacked the TCRαβ+CD4+CD8+ cells in this layer. They had a loss of Roryt+ innate lymphoid cells in the lamina propria. Epidermal TCRγδ+ cells were also absent in the Vav-Cre Arnt fl/fl mice. We also noted reductions in conventional natural killer cells in the lamina propria of Vav-Cre Arnt fl/fl mice compared with wild type controls, which has not been reported in AHR null mice. Interpretation ARNT is crucial for establishing intraepithelial lymphocytes, lamina propria innate lymphoid cells, and epidermal TCRγδ+ cells. These data suggest that AHR–ARNT complexes control the development and survival of lymphocytes at barrier surfaces. ARNT also seems to have a role in conventional natural killer cells in the lamina propria independently of the AHR. Funding Wellcome Trust.