Within the lymphoid compartment, B and T cells that deliver adaptive immunity are well recognized as essential players in the clearance of pathogens and development of immunological memory. In contrast, myeloid cells and other innate lymphocytes are critical players in the early stages of an immune response, but are not thought to develop into long-lived memory cells that can participate in recall immunity. An open question remains as to whether any innate immune cells show properties consistent with immunological memory. Such ‘memory’ cells could provide a novel avenue for immune manipulation against pathogens for prevention or treatment of disease. Innate lymphoid cells (ILCs) are a recently described family of lymphoid effector cells that have important roles in immune defense, inflammation and tissue remodelling. It has been proposed that ILCs represent ‘innate’ homologues of differentiated effector T cells and they have been categorized into three groups (ILC1, ILC2, ILC3) that produce T helper (TH)-type cytokines (such as interferon-g, IL-5/IL-13 and IL-17/IL-22, respectively). In particular, ILC3 are highly enriched at mucosal sites, promoting barrier function and commensal microbial containment. How the functional competence of ILCs is established during the lifespan of an individual is unclear and how ILCs exert their multitude of functional roles during normal homeostasis and under inflammation or infection is unknown. Recently, NK cells have been proposed to possess ‘adaptive’ features thereby blurring the lines between innate and adaptive roles of ILCs and B/T cells, respectively. While NK cell memory remains a matter of debate, these reports do raise the question about whether ILC subsets can generate a similar degree of adaptation to pathogens and whether ILCs that have experienced pathogens show evidence of functional immunological ‘memory’. This proposal will address two novel and important aspects of innate lymphoid cell (ILC) biology: first, the notion of immunological ‘memory’ as it applies to group 3 innate lymphoid cells, and second, the cellular behavior of ILC3 under steady-state conditions and during inflammation and defense against infection by a model enteropathogen. These two intertwined objectives will be addressed by three complementary teams (Di Santo, Bousso, Frankel) having the required expertise in ILC biology, intravital microscopy and microbiology of C. rodentium infection, respectively. Understanding how commensal and pathogen encounter shapes the homeostasis and functionality of ILC subsets could lead to novel approaches that could enhance mucosal defense.