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The role of innate lymphoid cells in regulating intestinal inflammation

Periodic Reporting for period 1 - Tbet ILC JFN (The role of innate lymphoid cells in regulating intestinal inflammation)

Reporting period: 2015-05-01 to 2017-04-30

The gut is a complex organ, and many aspects of human health depend on proper gut function. There are three main compartments in the gut: (1) the epithelial layer, which forms a barrier, like the skin, against the outside environment; (2) the immune system, which protects the body from infections; and (3) the microorganisms that live in our gut, collectively known as the gut microbiota. Inappropriate interactions between these three compartments can impair gut functioning and affect other organs as well, and such events have been associated with the development of several diseases such as cancer, diabetes, obesity and inflammatory bowel disease (IBD). These diseases constitute a significant public health and economic problem.
The aim of this project was to study a specific type of immune cells that are abundant and have important functions in the gut, called innate lymphoid cells (ILCs), and understand their role during intestinal disease. There are different sub-populations of ILCs, some that can protect against gut infections, whereas others can promote intestinal inflammation. For example, Crohn’s Disease patients often accumulate a particular sub-population of ILCs, called ILC1s, in their inflamed gut, suggesting they play a role in causing this disease.
To be able to study ILCs in the gut environment and understand how they interact with the epithelial cells of the intestine, we developed a novel in vitro model. In our model, we start with a very small piece of the gut that contains stem cells, which can grow and become all the functional adult cells of the intestine. These stem cells are grown under very precise conditions and create three dimensional mini-guts in a dish, called intestinal organoids. We built upon previous studies that studied how to grow these intestinal organoids to define the conditions that enable the addition of immune cells into the mini-guts. Using this new system, we can now for the first time study how the immune cells, particularly ILCs, develop in the gut environment using an in vitro model.
Our results show that the intestinal organoids are able to support the development and differentiation of ILCs in similar ways as if the cells were developing inside the body. Interestingly, we found that adding ILCs to the organoids is not only important for the immune cells but also promotes the differentiation of the epithelial cells.
At the moment, we are also expanding upon our mouse studies and are setting up cultures using samples from patients with intestinal disease (starting from gut biopsies as a source of intestinal stem cells, and blood or intestinal immune cells as a source of ILCs) with the goal to better translate our studies to the human setting for further patient benefit.
This work has been presented at several seminars and conferences and we are preparing a manuscript for publication
Our novel system enables the study of how immune cells communicate with intestinal epithelial cells in both humans and animal models. Furthermore, we plan to expand our system to also include the microbial compartment (microbiota). Therefore, the methods developed as part of this project are great tools to identify novel pathways that regulate the interaction between the three gut compartments (epithelium, immune system and microbiota) and to test the impact of drugs or other therapies on these interactions. As the communications between these three gut components are critical for gut and systemic health, the use of our model could lead to the discovery of novel molecules that may be used as targets to treat diseases associated with intestinal inflammation and thus could improve patients’ lives.
Novel co-culture system of immune cells on intestinal organoids.