Origin and function of intestinal epithelial tuft cells as effectors of type 2 immune responses – TUFTEFF

The intestinal epithelium represents the principal interface between our organism and the outside world (approximately 200 square meters). Whereas the main function of the intestinal epithelium consists in absorbing nutrients, this epithelium is also in direct contact with the highly variable composition of the luminal content, containing potentially harmful compounds (mutagens, allergens, toxic substances) as well as microbes and parasites. The importance of the barrier function of the intestinal epithelium is reflected by the presence of 70% of the body’s total immunocytes in the gut.
The intestinal epithelium is composed of at least six differentiated cell types, including nutrient absorbing enterocytes, goblet cells that secrete a protective mucus layer, enteroendocrine cells that produce a variety of hormones regulating digestion, and Paneth cells with both antimicrobial and stem cell niche functions. An additional cell type, called microfold (or M cells), covers the surface of the gut mucosa-associated lymphoid tissue. Finally, intestinal epithelial tuft cells, a rare cell type identified in the 1970s have long been studied by the Jay lab but the extensive characterization of this lineage was delayed by the absence of specific markers. Recently, the association of the Jay and Taylor teams discovered the first tuft cell function, revealing its essential role in the initiation of type 2 immune responses during parasite infections. Tuft cells produce IL25, a specific cytokine called alarmin, which is responsible for the establishment of the immune response through the recruitment of type 2 T helper (Th2) and innate lymphoid cells (ILC2). This work, published in 2016 in the journal Nature (Gerbe et al., 2016), led to a better understanding of the interactions and functional cooperation between the epithelial compartment and the immune system, allowing the organism to defend itself against parasites.
In the project proposed here, we will use new models to elucidate the function of tuft cells following initiation of type 2 immune responses, integrating the co-regulation and functional crosstalk between the intestinal epithelium and the dynamics of the immune response to build an integrated model of the type 2 response.