EDITORIAL published: 17 June 2020 doi: 10.3389/fimmu.2020.01233 Editorial: The Role of Innate Lymphoid Cells in Mucosal Immunity Jessica G. Borger 1*†, Graham Le Gros 2† and Joanna R. Kirman 3† 1 Department of Immunology and Pathology, Central Clinical School, Monash University, Alfred Research Alliance, Melbourne, VIC, Australia, 2 Allergic & Parasitic Diseases Programme, Malaghan Institute of Medical Research, Wellington, New Zealand, 3 Department of Microbiology & Immunology, University of Otago, Dunedin, New Zealand Keywords: ILC, NK cell, mucosal, immunity, lung, gastrointestinal tract, genitourinary tract Editorial on the Research Topic The Role of Innate Lymphoid Cells in Mucosal Immunity Innate Lymphoid Cells (ILCs) are tissue-resident innate cells that are deeply integrated within mucosal tissues and play a critical role in tissue homeostasis and inflammatory processes. The collection of articles in this Frontiers Research Topic investigates and discusses the new and emerging roles of ILCs in mucosal immunity. The field of ILC biology has increased exponentially in recent years. Although the scientific Edited and reviewed by: community had been aware of the existence of certain innate cells of lymphoid origin for many Marina Cella, Washington University School of years, it has only been in the past decade that the full extent of the ILC family and their Medicine in St. Louis, United States wide-reaching biological roles has been recognized. As the field expanded, to avoid confusion due to the different names being used in the literature for the same ILC subsets, in 2013 it was *Correspondence: Jessica G. Borger proposed that ILCs should be divided into three broad lineages based on specific transcription [email protected] factor expression and the cytokines they produce. Group 1 (ILC-1) express T-bet and produce IFN- γ; Group 2 (ILC-2) express GATA-3 and produce IL-5, IL-4, and IL-13; and Group 3 (ILC-3) express †ORCID: RORγ t and produce IL-17 and IL-22 (1). These groups parallel the transcriptional and functional Jessica G. Borger characteristics of T helper 1 (Th1), Th2, and Th17 conventional T cells, respectively. Like T helper orcid.org/0000-0003-0704-1254 Graham Le Gros subset plasticity, there is heterogeneity within the different ILCs groups, and some overlap between orcid.org/0000-0002-5721-0442 the subsets. Joanna R. Kirman When comparing studies, it is important to recognize that methods to identify and orcid.org/0000-0002-4802-7048 categorize ILCs and their subsets vary from laboratory to laboratory. The lineage cocktail used to identify non-ILCs is the first potential source of variation between studies. This may result in Specialty section: contamination of ILCs and account for differences in the numbers of ILCs in different studies This article was submitted to (2). The molecules used to categorize ILCs also vary and can greatly influence the number of cells NK and Innate Lymphoid Cell Biology, identified in each subset; some studies use transcription factors to categorize ILCs, whilst others a section of the journal rely on the presence or absence of specific cell surface molecules. Frontiers in Immunology Unlike their adaptive counterparts, activation of ILCs is not modulated by genetically rearranged Received: 04 May 2020 antigen receptors. Rather, in the absence of conventional antigen recognition, ILCs respond directly Accepted: 18 May 2020 or indirectly to a diverse array of pathogen- and host-derived stimuli including stress-related Published: 17 June 2020 neuropeptides and hormones, cytokines, and metabolites (Jacquelot et al.). Due to their integration Citation: in tissues at barrier surfaces, and their ability to respond directly to signals without the requirement Borger JG, Le Gros G and Kirman JR (2020) Editorial: The Role of Innate for antigen presentation, ILCs are poised to respond rapidly to pathogens and tissue injury. This Lymphoid Cells in Mucosal Immunity. response is facilitated by a transcriptional program that enables phenotypic and functional plasticity Front. Immunol. 11:1233. of ILCs such that they can mediate and regulate tissue homeostasis, morphogenesis, metabolism, doi: 10.3389/fimmu.2020.01233 repair and regeneration. Frontiers in Immunology | www.frontiersin.org 1 June 2020 | Volume 11 | Article 1233 Borger et al. ILCs in Mucosal Immunity ILCs are located throughout the body, though they are and prevent immunopathology without compromising concentrated at barrier sites, including the skin and mucosal infection control. surfaces. ILCs in the skin are important for regulating and One such host-derived signal is S1P, a blood-borne bioactive maintaining epithelial and stromal cells and maintaining skin lysosphingolipid which binds to the S1P receptor 1 (S1PR1) barrier homeostasis. Although skin ILCs are not covered in to promote lymphocyte egress from the secondary lymphoid this Research Topic, understanding how their unique effector organs. Until recently, the effects of S1P and pharmacological functions may underlie their contribution to the pathogenesis agonists of S1PR1 on ILCs was unknown. Such agonists of inflammatory skin disorders such as dermatitis, psoriasis and include fingolimod, an immunomodulatory drug approved to immunity remains an exciting area for future investigation. modify the autoimmune disease multiple sclerosis (MS). In this This Research Topic comprehensively addresses the role Research Topic, Eken et al. reveals that ILCs express S1P1R of ILCs in maintaining tissue homeostasis at mucosal sites and administration of S1P agonists including fingolimod, drives including: the maternal and fetal compartments (Miller et al.; ILC-penia in MS patients and decreases ILC accumulation in Vacca et al.), lung (Ardain et al.; Borger et al.), gut (Vojkovics the secondary lymphoid organs of mice. Notably, long-term et al.), adipose tissue (Bénézech and Jackson-Jones), and kidney administration of fingolimod in mice led to decreased ILC3s in (Cameron et al.). ILCs function within these mucosal tissues is the small intestine. This study characterizes a further mechanism regulated through a delicate and complex cross-talk between the by which ILCs can sense and respond to host-derived signals to immune system and the signals received from the physiological maintain tissue homeostasis. systems of the body. This cross-talk requires an exquisite balance to maintain homeostasis and when appropriate to respond to environmental cues to control infection and restore tissue ILCS IN THE RESPIRATORY TRACT damage (Jacquelot et al.). During infection, ILCs are sensitive to diverse environmental The lung is considered a non-lymphoid mucosal organ signals and are critical for regulating responses to commensal comprising an innate cell network of epithelial cells, bacteria (Castleman et al.) and pathogens including bacteria macrophages, and dendritic cells, all crucial for maintenance (Jacquelot et al.), helminthic parasites (Bouchery et al.; Löser of immune homeostasis and the initiation of inflammatory et al.), and viruses (Ardain et al.; Panda and Colonna; Trittel processes. In addition, ILCs, which although only comprise a et al.). Indeed, understanding how the dysregulation of ILC small proportion of the total immune cells in the lung, have been responses can lead to chronic inflammatory diseases including: shown to promote lung homeostasis and contribute to disease allergy (Helfrich et al.; Panda and Colonna) and asthma processes. In mice, ILC2s are the predominant ILC subset in the (Ardain et al.; Borger et al.), chronic obstructive pulmonary lung (3) and in this Research Topic, Helfrich et al., provides a disease (COPD) (Ardain et al.; Borger et al.; Panda and comprehensive review on the contribution of ILC2s to allergic Colonna), and pulmonary fibrosis (Ardain et al.); as well as airway inflammation including allergic asthma, obesity-induced autoimmune diseases such as inflammatory bowel disease (IBD) asthma, and rhinosinusitis. (Vojkovics et al.), colitis (Panda and Colonna) and Crohn’s Helfrich et al. considers the effect of experimental and disease, is a consistent theme within this Research Topic. ILCs therapeutic strategies that are employed to ameliorate respiratory also influence the development of mucosal tumors, such as inflammation on ILC responses in the lung. Corticosteroids and colorectal cancer (Loyon et al.). Some ILC subsets play a pro- β2-agonists are common treatments for asthmatic patients and tumorigenic role; others appear to have a protective role through β2 adrenergic receptors are expressed by both human and murine promotion of anti-tumor responses or by limiting damage to ILC2s. The ILC2s respond β2-agonists by reducing proliferation tissue (Loyon et al.). Although many mechanisms and fine and effector function, suggesting that targeting ILC2s early in details of the interplay between ILCs and their environment disease could also block initiation of respiratory inflammation remain to be elucidated, it is clear that ILCs are critical for and redirect ILC2 activity Helfrich et al.. protecting mucosal barriers against communicable and non- Although the role of ILC2s in Th2 allergic airway responses communicable disease. is well-supported, the contributions of ILCs to chronic lung inflammation are poorly understood. In this issue Borger et al. and Panda and Colonna review the contribution of ILCs to REGULATION OF ILCS chronic pulmonary diseases. Dysregulation of ILCs and their ability to respond to changing local tissue environmental cues The physiological regulation of