Interleukin-22 Regulates Immunity, Inflammation and Tissue Homeostasis at Mucosal Sites

At mucosal sites, a single layer of epithelial cells separates the connective tissues of the mammalian body from the external environment. The gastrointestinal tract is the largest mucosal surface exposed to the environment and is colonized with an estimated 300 trillion beneficial commensal bacteria. These properties of mucosal sites help facilitate critical biological processes, including nutrient absorption, gas exchange and excretion of wastes, yet also renders mucosal sites particularly vulnerable to infection and inflammation. In order to maintain a state of health, complex immunoregulatory networks have evolved at mucosal sites to promote immunity, limit inflammation and maintain tissue homeostasis. Interleukin (IL)-22 is a member of the IL-10 cytokine family that is produced by both innate and adaptive immune cells, and acts directly on the mucosal epithelium to promote anti-microbial, reparative and inflammatory responses. Chapter 2 of this thesis examines the role and regulation of IL-22 production by innate lymphoid cells (ILCs) in promoting immunity to the enteric bacterial pathogen Citrobacter rodentium. The data identify that following infection, IL-23 promotes an IL-22+ CD4+ ILC response that is necessary and sufficient to promote enteric immunity, limit bacteria dissemination and prevent host morbidity and mortality. In addition to pathogenic bacteria, loss of containment and peripheral dissemination of beneficial commensal bacteria results in dysregulated systemic immune cell homeostasis, and is a hallmark of numerous chronic human diseases. Chapter 3 of this thesis demonstrates a novel role for IL-22-producing ILCs in containing intestinal commensal bacteria, limiting peripheral dissemination and induction of systemic inflammation. Finally, studies have identified both pathologic proinflammatory and beneficial tissue-protective functions for IL-22 in distinct models of infection and inflammation. Chapter 4 of this thesis identifies that the pathologic proinflammatory versus tissue-protective properties of IL-22 in a model of airway inflammation are regulated by Th17 cell-derived IL-17A. Collectively, studies presented in this thesis identify novel regulatory and functional aspects of IL-22 and ILCs, and demonstrate a critical role for this pathway in the immunoregulation of tissue homeostasis at mucosal sites