FOR2599Project 5

Signals orchestrating innate type 2-mediated immunity

Summary

ILC2 are tissue-resident innate lymphocytes that are an important early source of type 2 cytokines such as IL-5 and IL-13 and, therefore, contribute to the defence against worm infections. However, if inappropriately stimulated, ILC2 have also been linked to the pathogenesis of asthma and allergies. It is a new paradigm that organ-resident ILC may play important roles in tissue homeostasis and tissue repair. In the context of ILC2, it has been demonstrated that they promote tissue repair through release of EGF family proteins and intestinal epithelial cell differentiation towards the secretory lineage. Among the major outstanding questions in ILC2-mediated immunity are the molecular networks by which ILC2 control epithelial cell differentiation. We and others have identified ILC-committed progenitors (referred to as CHILP) and we have shown that the transcriptional programs of ILC2 resemble that of Th2 cells. However, the signals driving ILC2 fate decisions are unknown and differ from those operative in Th cells. Our FOR2599 addresses these two major challenges. We interrogate the role of ILC2 for epithelial homeostasis and their role in controlling epithelial fate decisions towards the secretory lineage. And we aim to identify the signals that drive the differentiation of ILC2 from uncommitted progenitors (i.e., CHILP).