Signals orchestrating innate type 2-mediated immunity
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).
Differentiation of group 2 innate lymphoid cells and their role during homeostasis and type 2 inflammation
Type 2 immune responses protect against infections with macroparasites and promote metabolic homeostasis in adipose tissue but can become detrimental when triggered against non-infectious environmental stimuli. The cytokines IL-25, IL-33, and TSLP are strong activators of type 2 inflammation in tissues via stimulation of group 2 innate lymphoid cells (ILC2s) and other innate immune cells, such as eosinophils, mast cells, basophils and alternatively activated macrophages (AAMs), resulting in a cytokine milieu, which promotes differentiation of T helper 2 cells and secretion of immunoglobulin E. Although ILC2s become quickly activated after an immune response is initiated, their precise role in orchestrating type 2 inflammation remains elusive due to the limitations in specifically targeting this population.
Our research has recently identified neuromedin U receptor 1 (Nmur1) as a marker selectively expressed by ILC2s but not by T cells, B cells, eosinophils, or mast cells in steady-state and during type 2 inflammation. Using the Nmur1 promoter as a driver, we have generated genetic tools to interfere with ILC2 specifically in otherwise lymphoreplete mice.
We propose to use the new genetic tool to investigate ILC2-mediated immunoregulation by immunophenotyping and single-cell state-of-the-art sequencing technology. We will further explore the signal circuits by which ILC2 program tissues to maintain barrier function and integrity. A subaim is devoted to understand the contribution to ILC2-controlled circuits for the colonization with the commensal microbiota. Furthermore, this new tool will also allow us to investigate the ontogeny, plasticity, and heterogeneity of ILC2. Altogether, these data will shed light on the function, development, and dynamic of ILC2s subsets and their crosstalk with other immune and non-immune cells in tissues.
Exploiting the possibilities of this newly generated genetic tool, this proposal now aims to systematically investigate immunoregulation mediated by ILC2s. Delineating immunoregulation by ILC2s will be crucial to understand how type 2 immune responses are orchestrated and discover novel molecular pathways, which can be harnessed for prevention and therapy of atopic diseases.