DOP34 Deciphering immune-epithelial interactions in health and in Inflammatory Bowel Disease

Abstract

Abstract Background Intestinal homeostasis is dependent on appropriate interactions between various compartments including immune, mesenchymal, neural, epithelial and bacteria cells. Disrupt of these interactions has been associated with the development of Inflammatory Bowel Disease (IBD). Using intestinal organoids as a starting point, we built complexity into this model by adding other cellular components to be able to study these interactions in health and disease. One of the key immune players in the intestine is Innate Lymphoid Cells (ILC). ILC precursors (ILCP) migrate to mucosa where they mature, promote homeostasis, and provide a potent, antigen-non-specific sources of cytokines. Deciphering what local stimuli drive the final stages of ILCP maturation in these tissues remains a pressing question, as ILC frequencies can become dysregulated in IBD. Methods Here, we develop and use co-cultures gut organoids with Innate Lymphoid Cells precursors (ILCP) and with mature intestinal Innate Lymphoid Cells (ILC). Results Harnessing these versatile models, we demonstrate that epithelial cells provide a complex niche capable of supporting the final maturation of all subsets including ILC1, ILC2, ILC3 and Natural Killer (NK) cells, Notably, organoid identity was sufficient to robustly recapitulate tissue-specific ILC imprints and frequencies, even in the absence of microbial stimuli, other cell types, or cytokine supplementation. In addition, we show that human gut ILC1 drive intestinal and extracellular matrix remodelling through production of TGFβ. This indicates the potential impact of ILC1 accumulation in IBD patients in driving intestinal cancer and fibrosis, two sequelae of IBD. Finally, we identify a new module of interaction between ILCs and the intestinal epithelium: goblet cells provide Notch ligands that are essential for maintenance of NC3R+ ILC3 and for their production of IL-22. In turn, ILC3 drive intestinal epithelial cells towards a secretory phenotype. Conclusion Taken together, our work provides unprecedented insight into in situ ILC maturation, which we show to be driven by epithelial signals, and into ILC function through deciphering new modules of ILC-epithelial interaction in health and IBD.