Aryl-hydrocarbon receptor-driven responses of innate lymphocytes

Abstract Innate Lymphoid Cells (ILCs) play significant roles during immune responses to infection at barrier sites and in the control of tissue damage and repair. In addition, ILCs have been involved in several pathologies, including exacerbated inflammation and carcinogenesis. However, understanding the contribution of distinct ILC subsets and modules of their regulation in both homeostasis and disease, is still incomplete. The Aryl-hydrocarbon Receptor (AhR) is a ligand-induced transcription factor that binds various exo- and endogenous polycyclic hydrocarbons and induces transcription of numerous target genes involved in development, cell differentiation and immune response. Here, we show that subsets of NKp46-expressing ILCs, including natural killer (NK) cells and helper ILC1, express AhR and respond to stimulation with AhR ligands. Exposure of NK cells to the tryptophan degradation product kynurenine, an endogenous AhR ligand, induced changes in global gene expression and primed NK cells for enhanced effector responses, including cytokine secretion and migration. In the context of diet-induced chronic liver damage, NK cells accumulated in the liver in an AhR-dependent manner. Conditional AhR deletion abolished NK cell accumulation, which correlated with reduced liver damage. In contrast to NK cells, liver resident helper ILC1 required AhR for the development and/or maintenance. In conclusion, the AhR is expressed by ILC1 subsets and differentially affects their development and effector responses. This might impact ILC1-driven responses in the context of chronic liver damage and could be of significance for liver tissue regeneration.