INTESTINAL TUFT CELLS: NEW PLAYERS IN INTESTINAL IMMUNE REGULATION – IMMUNOTUFT

Cell biology, genetics, cell sorting, RNA-Seq, immunohistochemistry, cell culture

We have identified the first function of the intestinal tuft cells, which constitute an essential relay to activate the immune response after a parasite infection. We have also identified the first transcription factor required specifically for the differentiation of the tuft cells.

The function of tuft cells in type 2 responses in the context of parasite infections suggests a potentially important role in allergies and asthma.

Gerbe F., Sidot E., Smyth D. J., Ohmoto M., Matsumoto I., Dardalhon V., Cesses P., Garnier L., Pouzolles M., Brulin B., Bruschi M., Harcus Y., Zimmermann V. S., Taylor N., Maizels R. M. and Jay P. : Intestinal epithelial tuft cells initiate type 2 mucosal responses to helminth parasites. Nature, vol. 529 : 226-230 (2016).

Living organisms need to adapt to their permanently changing environment. The intestinal epithelium represents the main interface between our organism and its environment, presenting 200 square meters after development of the villi/microvilli surfaces. The content of the intestine can vary tremendously, not only in the quantity and nature of nutrients, but also in potentially harmful compounds (mutagens, allergens, toxic substances), microbes and parasites. In humans, 70% of the immunocytes are located in the intestine, highlighting the importance of the intestinal epithelium as an entry site for exogenous compounds and invading organisms. However, the sensing and sampling of luminal materials by epithelial cells, as well as the molecular pathways involved in the crosstalk between intestinal epithelial cells and the underlying immune cells have only been partially deciphered.
Our current understanding of the defence role of the intestinal epithelium involves (i) non-immune mechanisms, including secretion of a protective mucus layer; (ii) innate factors such as lysozyme, alpha- and beta-defensins, and resistin-like molecule-ß, which are produced by Paneth cells in intestinal crypts; and (iii) sampling and translocation of luminal antigens by specialised epithelial cells such as Microfold (M) cells that cover the mucosal lymphoid follicles of the intestine, for presentation to underlying dendritic cells and lymphocytes. Intestinal epithelial cells (as a whole) are also known to play important roles in the induction of T cell immunity, and more specifically, in Th2 immune responses during parasitic infections. T cells differentiated towards a Th2 phenotype secrete cytokines such as IL-4, IL-5, IL-13 and IL-21 and these effector lymphocytes are critical in protecting the organism against parasitic worms such as helminths. Notably though, they also promote pathologic responses associated with allergy.
In this project, we will address the function of tuft cells in conditioning intestinal immunity. This cell type displays a unique morphology including a well-developed apical tuft of blunt microvilli that projects into the gut lumen and was first discovered more than half a century ago. However, due to the lack of specific markers, tuft cells have been systematically overlooked in functional studies of intestinal epithelial function and in phenotypic analyses of genetically engineered mouse models. Their only known or supposed functional features are their ability to produce signalling molecules such as prostanoids and opioids, and their potential stem cell properties. We recently characterised intestinal tuft cells and genetically demonstrated that they constitute a distinct cell lineage in the intestinal epithelium, originating from the Lgr5-expressing crypt base columnar (CBC) stem cells. As a result, the intestinal epithelium, which was thought to contain four differentiated cell types (nutrient-absorbing enterocytes, mucus producing goblet cells, hormone-producing enteroendocrine cells, and antimicrobial peptide-producing Paneth cells), actually includes a fifth cell type, whose functions remain to be elucidated. Previous data from our laboratory and others suggest that tuft cells sense the intestinal luminal content and regulate the behaviour of neighbouring cells and intestinal epithelial stem cells. Importantly, our most recent data point to a critical role for intestinal tuft cells in regulating gut immune responses. The main aim of this project is to characterize the function of intestinal tuft cells in the defence of the organism at the immune system/ environment interface.