Group 2 innate lymphocytes at the interface between innate and adaptive immunity Martijn J. Schuijs 1 , Timotheus Y.F. Halim 1 1 Cancer Research UK – Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, United Kingdom Corresponding author contact information: CRUK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, United Kingdom Tim.Halim@cruk.cam.ac.uk Short Title: ILC2 responses in innate and adaptive immunity Keywords: Innate lymphoid cells; ILC2; Type-2; T helper cells; Th2 Abstract: Group 2 innate lymphoid cells (ILC2) are innate immune cells that respond rapidly to their environment through soluble inflammatory mediators and cell- to-cell interactions. As tissue-resident sentinels, ILC2 help orchestrate localized type-2 immune responses. These ILC2-driven type-2 responses are now recognized both in diverse immune-processes, different anatomical locations, and homeostatic or pathological settings. ILC2-derived cytokines and cell- surface signalling molecules function as key regulators of innate and adaptive immunity. Conversely, ILC2 are governed by their environment. As such, ILC2 form an important nexus of the immune system and may present an attractive target for immune modulation in disease. 1. Introduction In 2010, murine group 2 innate lymphoid cells (ILC2) were formally described as a novel innate lymphoid cell (ILC) population that promoted type-2 immunity 1-3 . ILC2 are tissue-resident immune cells important for orchestrating local type-2 inflammation, found to be enriched at mucosal and barrier surfaces 4 . Functionally, ILC2 are mainly described for their role in promoting protective immunity to helminth infections, tissue repair, metabolic homeostasis, as well as allergic inflammation 5-7 . ILC2 belong to a larger family of ILC that parallel the adaptive immune system in function, but lack antigen specificity (for a review of ILC-lineages, see ref. 8 ). ILC distinctively lack antigen-specific receptors and are activated in an antigen-independent manner. This enables ILC to rapidly respond to changes in their microenvironment without the need for adaptive immune cell priming 9 . More specifically, ILC express germline-encoded inhibitory or activating