Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS


NUTRIMMUNE Informe resumido

Project ID: 311377
Financiado con arreglo a: FP7-IDEAS-ERC
País: Germany

Mid-Term Report Summary - 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 allowing adaptation of multicellular organisms to their environments (i.e., microbial communities, nutrients). These lines of work have established new insights into host-microbe interactions and have assigned new roles to components of the immune system involved in “sensing” the environment for maintaining barrier function and organ homeostasis. Failure of such homeostatic programs have been linked to susceptibility to intestinal infection or to chronic inflammation causing debilitating human diseases such as inflammatory bowel diseases (e.g., ulcerative colitis, Crohn’s disease) or inflammation-induced intestinal cancer. While the contribution of the microbiota to intestinal homeostasis and to many relevant diseases has been documented, 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 are widely unknown. We have recently found that the aryl hydrocarbon receptor (AhR), a transcription factor activated by various environmental ligands, is required for the development of innate immune system components (Kiss, Science 2011). The AhR serves as a sensor for dietary AhR ligands that are contained in high concentrations in vegetables of the Brassicaceae family (e.g., broccoli, brussel’s sprouts). Specifically, a subset of innate lymphocytes (ILC) referred to as group 3 ILC (ILC3) that is involved in maintaining epithelial barrier function and resistance to intestinal infections, required diet-induced AhR signals for its maintenance and function. We aim to systematically define the role of diet-induced changes for the function and differentiation of mucosa-associated innate lymphocytes and to uncover how ILC regulate epithelial adaptation by controlling niche support for intestinal epithelial stem cells. In partial fullfillment of our aims, we have made progress in several of these areas. (1) We have uncovered a new role of the ILC3-derived cytokine IL-22 for the protection of mice against rotavirus infection, a virus with strict tropism to intestinal epithelial cells. Rotavirus, a double-stranded RNA virus of the Reoviridae family is the leading cause of viral gastroenteritis in infants causing annually more than 500,000 fatalities worldwide. Our data identified IL-22 as a requirement for control of rotavirus replication. Surprisingly, epithelial repair and epithelial proliferation was not impaired in mice lacking IL-22, processes that have been previously linked to IL-22 signaling in epithelial cells. We identified a novel function of IL-22 as an amplifier of type III IFN (i.e., IFN-λ) signaling. Cooperation between the evolutionary related cytokines IL-22 and IFN-λ was required for optimal STAT1 activation and expression of interferon-stimulated genes (ISGs) which are needed to restrict virus replication. These results represent a significant advance in our understanding of how mucosal cytokine networks cooperate for efficient antiviral immunity, and they may inform the design of novel immunotherapies of virus infections that are sensitive to interferons. Our data uncover new paradigms for the protection of epithelial cells against virus replication by co-opting the action of two evolutionarily related cytokine receptors expressed by epithelial cells that cooperate to curtail virus replication in intestinal epithelial cells. (2) We had previously found that the maintenance of ILC3 depended on signaling of the AhR (Kiss, Science 2011). Conspicuously, not all ILC3 populations were equally dependent on the presence of AhR signals which may indicate the existence of AhR-dependent and AhR-independent ILC3 subsets. We found that a subset of ILC3 expressed the transcription factor T-bet. This was a surprising finding because it was widely believed that RORγt and T-bet regulate discrete cell fates and are not co-expressed. T-bet instructed the expression of T-bet target genes such as interferon-γ (IFN-γ) and of the natural cytotoxicity receptor NKp46. The production of IFN-γ by T-bet-expressing ILC3 was essential for the release of mucus-forming glycoproteins required to protect the epithelial barrier during Salmonella enterica infection. Co-expression of T-bet and RORγt, which is also found in subsets of T helper 17 cells, may be an evolutionary conserved transcriptional program that originally developed as part of the innate defence against infections but that also confers an increased risk of immune-mediated pathology. (3) ILCs have been categorized into three distinct groups, transcriptional circuitry and effector functions of which strikingly resemble the various T helper cell subsets. We identified a common, Id2-expressing progenitor to all interleukin 7 receptor-expressing, ‘helper-like’ ILC lineages, the CHILP. Interestingly, the CHILP differentiated into ILC2 and ILC3 lineages but not into conventional natural killer (NK) cells that have been considered an ILC1 subset. Instead, the CHILP gave rise to a peculiar NKp46+ IL-7Ralpha+ ILC lineage that required T-bet for specification and was distinct of cNK cells or other ILC lineages. Such ILC1s co-produced high levels of IFN-γ and TNF and protected against infections with the intracellular parasite Toxoplasma gondii. Our data significantly advances our understanding of ILC differentiation and presents evidence for a new ILC lineage that protects barrier surfaces against intracellular infections.

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