Cul5 regulates lung ILC2 cells during helminth infection

PROJECT SUMMARY Type 2 immune responses provide protection against damaging parasitic helminth infection. Helminth infections, of which there are currently 1 billion world-wide, can cause tissue damage, generalized immunosuppression, malnutrition and anemia. While most helminths reside in the intestine, a critical stage of the life cycle of many helminths involves transit through the lung. Thus, anti-helminth type 2 immune responses are observed in the lung and GI tract. While type 2 immune responses can be advantageous during worm infection, in some individuals, immune cells inappropriately target innocuous allergens and drive devastating and potentially life- threatening allergic disease. Thus, understanding how type 2 immune responses are controlled may provide new therapeutic approaches for eradicating worm infection or treating allergic disease. This proposal details a novel regulatory circuit in a recently discovered subtype of IL-18 receptor expressing (IL-18R+) ILC2 cells in the lung. This regulatory circuit helps to prevent immune cell mediated lung inflammation as helminth larvae transit the lung. At the center of this regulatory circuit is the E3 ubiquitin ligase Cul5. Based on our preliminary data, we hypothesize that Cul5 limits IL-18R signaling in ILC2 cells in the lung to restrict IL-18R+ ILC2 numbers and recruitment of tissue damaging neutrophils. Information gained from these studies will broaden our understanding of functionally distinct ILC2 subsets and how they behave in different tissues, and aid the design of therapies that enhance or inhibit Cul5 activity. In Aim 1 we will determine how Cul5 expression in IL-18R+ ILC2 cells impacts the clearance of helminth larvae from the lung, recruitment of larvae killing neutrophils, and persistent lung inflammation. In Aim 2, we will determine how Cul5 regulates signaling downstream of the IL-18 receptor and features of the Cul5 ubiquitin complex important for this function, and in Aim 3 we test whether Cul5 regulation of ILC2 function is limited to the lung or also occurs at other mucosal barrier surfaces. With our combined expertise in ubiquitin ligase function, type 2 immune responses, neutrophils, ILC2 biology and N. brasiliensis infection, we are uniquely poised to uncover cytokine regulatory circuits in ILC2 subsets that will have a significant and long term impact on our understanding of how ILC2 cells initiate type 2 immune responses, and how regulatory circuits in these cells impact helminth clearance and immune cell mediated tissue damage. This information will aid future therapeutic targeting of Cul5 for treating helminth infection and allergy.