NUTRIMMUNE · NutrImmune: Nutrient-controlled molecular pathways instructing development and function of mucosa-associated innate lymphocytes

The last decade has witnessed an explosion of research into the molecular networks ensuring maintenance of a mutualistic relationship between microbes and host cell networks at mucosal surfaces. Failure of such homeostatic or adaptive programs lead to susceptibility to intestinal infections or to chronic inflammation causing debilitating human diseases such as inflammatory bowel diseases or inflammation-induced intestinal cancer. In contrast to the role of the microbiota and its composition, the role of nutrients for development and function of the intestinal immune system has been a matter of speculation owing to the fact that molecular sensors of dietary molecules were widely unknown. Given the broad impact of nutrients on metabolic diseases and human health, research into the question of how the power of nutrients can be harnessed for improving human health and for the prevention of disease is much warranted. We have recently found that the aryl hydrocarbon receptor (AhR) is required for the development and function of an innate lymphocyte subset (RORγt+ ILC) that protects against intestinal infections and inflammatory bowel disease (Kiss, Science 2011). AhR serves as a ligand-inducible transcription factor sensing plant-derived phytochemicals and directly controls expression of genes required for the maintenance of RORγt+ ILC. The data established the first molecular link between diets and the development of immune system components. Here, we will test our central hypotheses that (1) diets adapt the function of the intestinal immune system by controlling the pool size of innate lymphocytes, and that (2) RORγt+ ILC directly control epithelial homeostasis and adaptation by regulating niche programs that control intestinal stem cell population dynamics. These aims link nutrient-controlled function of innate lymphocytes to the processes regulating organ homeostasis and may reveal new potential therapeutic strategies for intestinal diseases and cancer.