Regulation of the tuft-ILC2 circuit in the small intestine

Project Summary Parasitic worms (helminths) currently infect 1-2 billion humans and are the cause of widespread morbidity. Helminth infections of livestock result in large economic losses. Meanwhile, the incidence of allergies is increasing globally, but particularly in regions where helminths are absent. Although seemingly unrelated, helminths and allergens are immunologically linked as they both induce a type 2 immune response. The activation and regulation of type 2 immunity remain incompletely understood, especially in the small intestine (SI). We recently discovered that rare chemosensory epithelial tuft cells are required for anti-helminth immunity in the SI. Tuft cells activate group 2 innate lymphoid cells (ILC2s), which in turn secrete canonical type 2 cytokines to coordinate hallmarks of type 2 immunity, such as eosinophilia and tissue remodeling. Specifically, IL-13 signaling in epithelial progenitors biases their lineage commitment towards tuft cells, leading to tuft cell hyperplasia during helminth infection and in mice colonized with Tritrichomonas protists. This tuft-ILC2 circuit is activated when tuft cells sense succinate secreted by Tritrichomonas, but the ligand and receptor mediating helminth sensing remain unknown. Additionally, while the cells and intercellular signals of the tuft-ILC2 circuit are emerging, the intracellular signaling pathways that regulate the circuit remain completely unknown, especially within the epithelium. In this proposal, we examine how POU2F3 is regulated to induce tuft cell hyperplasia (Aim 1), test the function of KIT signaling in tuft cells (Aim 2), and characterize novel tuft cell ligands and the intracellular signals they activate (Aim 3). In addition to helminth infection, the tuft-ILC2 circuit has recently been implicated in enteric virus infection and ileitis induced by bacterial dysbiosis. Therefore, the regulatory mechanisms uncovered by this project promise to identify therapeutic targets for the treatment of numerous SI pathologies.