Group 2 innate lymphoid cells (ILC2s) are recently characterized as a new subset of lymphoid cell populations, which play pivotal roles in inducing allergic inflammation, clearing infections, and repairing damaged tissues. They secrete type 2 cytokines including interleukins 5 and 13 and are controlled by transcription factors Gata3 and Ror?. These cells are present in both mouse and humans and are involved in various disease developments. However, the underlying cellular and molecular mechanisms of regulation remain largely unknown. Our long-term goal is to study the process of protein modification by the ubiquitin tagging in immune responses. We thus performed preliminary studies to explore the roles of E3 ubiquitin ligases in ILC2s by using conditional deletions of genes in mouse models, and found that the deficiency of VHL E3 ligase component results in defective development of ILC2s in the lungs, whereas loss of Fbw7, another E3 ligase component, caused defective differentiation in the bone marrow under steady state, and reduced lung ILC2 numbers upon allergen exposure. These preliminary studies indicate that the ubiquitin system is important for ILC2s, and allow us to hypothesize that they function at different stages of ILC2 differentiation via targeting the ubiquitination of their targets. To test this central hypothesis,we propose the following two major aims: Specific Aim 1: To study VHL in ILC2 maturation and function in the lungs. Specific Aim 2: To study Fbw7 in ILC2 development in the bone marrow and function in the lungs. We will use a combination of in vitro and in vivo feasible approaches, with complementary alternatives. The expected results will significantly move this field forward, and will have impact on the development of therapeutic methods and/or targets for inflammatory diseases and infection.