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

Final Report Summary - NUTRIMMUNE (NutrImmune: Nutrient-controlled molecular pathways instructing development and function of mucosa-associated innate lymphocytes)

Stand alone description of the project and its outcomes

The goal of my laboratory is to understand the molecular bases of how tissue homeostasis at mucosal surfaces is established. In particular, we thrive to understand how diets and the indigenous microbiota control the function of host cell networks. Failure of such adaptive processes leads to susceptibility to intestinal infections, chronic inflammation and inflammation-induced cancer. Colon cancer is one of the most common cancers worldwide with the highest incidence in Western-style countries (Australia, Europe, USA) suggesting an important role of lifestyle factors such as diets and environmental exposures. Thus, research into the environmental factors influencing mucosal homeostasis is an important socioeconomic and health care challenge of our days.

The focus of recent research has been to understand the mutual relationship between host cell programs and the indigenous microbiota. In contrast, the role of diets has been neglected mainly owing to the fact that molecular pathways for the sensing of nutrients and translating these signals into epithelial or immune cell function are largely unknown. Our recent work has exposed a molecular pathway of how innate lymphocyte function and development of intestinal lymphoid follicles are controlled by a sensor of plant-derived phytochemicals (Kiss, Science 2011). This sensor, the aryl hydrocarbon receptor (AhR), acts as a ligand-inducible transcription factor controlling the pool size and the function of mucosa-associated innate lymphocyte subsets. This proposal aims to systematically define the role of diet-induced changes for the function and differentiation of mucosa-associated innate lymphocytes and their interaction with the intestinal stem cell niche. This research has the potential to identify novel molecular pathways that can be harnessed for the prevention or therapy of intestinal infections or cancer.

Environmental genotoxic factors pose a serious and constant peril to the genomic integrity of cells at barrier surfaces with the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development. Genome integrity in epithelial stem cells is closely guarded by an evolutionary conserved, stem cell-intrinsic cellular response pathway, the DNA damage response (DDR). Interleukin 22 (IL-22) produced by innate lymphocytes is an important rheostat of the DDR machinery in intestinal epithelial stem cells. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations, and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in plants of the Brassicaceae family, to be a source of genotoxic stress in intestinal epithelial cells. Glucosinolate metabolites are ligands of the AhR and AhR signaling in innate lymphocytes controlled the amount of IL-22 produced. Our data identify a new homeostatic network that allows for on-demand production of IL-22 in response to genotoxic components contained in diets thereby protecting stem cells against perils to their genome integrity.

Environmental signals such s those provided by the indigenous microbiota shape many aspects of host physiology. Microbiota-derived cues are required to calibrate dendritic cells (DC) and other mononuclear phagocytes during the steady-state so that they can promptly respond to pathogen encounter with the provision of cytokine and chemokine cues and by priming of T cell responses. Here, we report that the indigenous microbiota controls the production of type I interferons (IFN-I) in the steady-state. Using genome-wide analysis of transcriptional and epigenetic states, we found that such microbiota-controlled tonic IFN-I receptor signaling in DC instructs a specific chromatin and metabolic basal state, poising DC for pathogen combat. However, such beneficial biological function comes with a trade-off. DC in such a poised basal state can prime unwanted T cell responses, a peril that is countered by barriers of peripheral tolerance. Our data provide a rationale for the evolution of mechanisms of peripheral tolerance to subdue such unwanted activities inherent to a poised basal state of DC.