Project Details
Projekt
Differentiation of group 2 innate lymphoid cells and their role during homeostasis and type 2 inflammation
Subject Area
Immunology
Term
from 2017 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 322359157
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, the precise role in orchestrating type 2 inflammation remains elusive due to the limitations in specific targeting this population.Our research has recently exposed 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 now generated BAC-transgenic mice, which expresses the reporter gene GFP and Cre under the Nmur1 promoter (Nmur1eGFP-2A-Cre). Our preliminary data show, that this mouse line allows gene targeting of ILC2 in vivo and will help to remove a major bottleneck in this field of research. We propose to generate ILC2-deficient mice by crossing Nmur1eGFP-2A-Cre mice to Gata3flox/flox mice, an essential transcription factor for ILC2s. We will employ high-fat diet and provoke atopic dermatitis (AD) by calcipotriol treatment to challenge the ILC2-deficient mice. The analysis of these mice in steady-state and in both disease models will be combined with immunophenotyping and single-cell state-of-the-art sequencing technology of innate and adaptive immune cells. 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 intense colonization with Staphylococcus aureus found in virtually all AD patients. By performing random barcode and fate-labeling starting from the CHILP (Id2CreERT2/+) or the ILC2 precursor (Nmur1eGFP-2A-Cre), we will be able to investigate ontogeny, plasticity, and heterogeneity of ILC2 in different tissue. Altogether, these data will shed light on the function, development and the 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 at steady-state and in the context of type 2 inflammation in the skin and adipose tissue. 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 the prevention and therapy of obesity and AD.
DFG Programme
Research Units
