CD45-mediated intestinal tuft cell sensing of the microbiome in health and disease

The mucosal surface of the gastrointestinal tract consists of a single layer of intestinal epithelial cells (IECs), which provides a physical barrier between our body and the outside world. Being the gut sentinels, IECs harbor an arsenal of immune-like functions, including pathogen sensing as well as antimicrobial peptide secretion to eliminate pathogens. Tuft cells are a specific sub-type of IECs, known to orchestrate a type-2 immune response as a result of parasitic infection, which is crucial for parasitic clearance. While it is established that tuft cells express a plethora of GPCRs including taste receptors, as well as immune related genes, the function of these genes within tuft cells is unclear. Specifically PTPRC, also known as CD45, was found to be expressed by tuft cells. CD45 was until recently thought of as an exclusive marker of the hematopoietic system. However, CD45’s function within tuft cells, and generally in immune cells, remains unknown. To unravel the role of CD45 within tuft cells, we generated a novel mouse model which allows to conditionally delete PTPRC in vivo. We utilized these Vilcre^ER CD45^flox mice together with advanced RNA-seq methods, to deeply characterize the impact of CD45’s expression within tuft cells, affected by both the immune and microbiome compartments in the intestine. We demonstrated that DSS-induced inflammation, as well as models of microbiome alterations, shift the tuft cell population towards a more inflamed phenotype, and alter CD45 expression. This study provides new tools to study CD45, and illuminates its importance in gut homeostasis and disease.