ILCADAPT · Innate lymphoid cells and tissue adaptation to changing metabolic needs

Border surfaces of vertebrate organisms are in constant exchange with their habitat. Host cell networks consisting of epithelial cells, stroma and tissue-resident immune cells continuously integrate signals from the environment, a process by which an organism becomes better suited to its habitat (i.e., adaptation). Our understanding of the molecular underpinnings of such homeostatic processes is in its infancy, yet they are decisive for proper organ function. Recently, we and others have identified homeostatic circuitry involving tissue-resident immune cells in the small intestine facilitating adaptation to changes in nutrient cargo. The goal of my laboratory is to capture these molecular networks and to investigate how their failure predisposes to diseases. This proposal aims to systematically define the role of mucosa-associated group 3 innate lymphoid cells (ILC3) and of the IL-22:IL-22BP module in tissue adaptation to changes in metabolic need via their interaction with intestinal stem cells, stromal cells and enteroendocrine cells (EEC). Answering these questions demands both focused and global experimental approaches as well as the use of new genetic models for targeting of ILC3 and for recording epithelial cell differentiation. Based on these considerations and on strong preliminary data, we have devised 3 Specific Aims that will allow an unprecedented analysis of ILC3-controlled tissue adaptation: (1) to understand intestinal ILC3-epithelial cell units regulating nutrient handling and systemic metabolism, (2) to test the role of ILC3 in intestinal adaptation to increased metabolic demand during pregnancy, and (3) to characterize a new immune-epithelial module consisting of EEC and IL-22-producing ILC3. We and others have demonstrated that ILC3 effector programs are highly conserved and are operative in humans. Thus, the anticipated results will carry tremendous implications for the prevention and therapy of metabolic diseases.