Suzanne M. Bal

Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The discovery of naïve-like ILCs suggests an ILC differentiation process that is akin to naïve T cell differentiation. Delineating the mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here, we showed that tonsillar ILCs expressing CD45RA lacked proliferative activity, indicative of cellular quiescence. CD62L distinguished two subsets of CD45RA ⁺ ILCs. CD45RA ⁺ CD62L ⁺ ILCs (CD62L ⁺ ILCs) resembled circulating naïve ILCs because they lacked the transcriptional, metabolic, epigenetic, and cytokine production signatures of differentiated ILCs. CD45RA ⁺ CD62L ⁻ ILCs (CD62L ⁻ ILCs) were epigenetically similar to CD62L ⁺ ILCs but showed a transcriptional, metabolic, and cytokine production signature that was more akin to differentiated ILCs. CD62L ⁺ and CD62L ⁻ ILCs contained uni- and multipotent precursors of ILC1s/NK cells and ILC3s. Differentiation of CD62L ⁺ and CD62L ⁻ ILCs led to metabolic reprogramming including up-regulation of genes associated with glycolysis, which was needed for their effector functions after differentiation. CD62L ⁻ ILCs with preferential differentiation capacity toward IL-22–producing ILC3s accumulated in the inflamed mucosa of patients with inflammatory bowel disease. These data suggested distinct differentiation potential of CD62L ⁺ and CD62L ⁻ ILCs between tissue microenvironments and identified that manipulation of these cells is a possible approach to restore tissue-immune homeostasis.

An inflammatory CD45RO ⁺ ILC2 population found in inflamed human nasal tissue is steroid resistant and linked to type 2 immunopathology.

T helper 2–skewed regulatory T cells in the skin use GATA3 to suppress local profibrotic type 2 cytokine production. See the related Research Article by Kalekar et al .

Recently, human ILCs that express CD117 and CD127 but lack CRTH2 and NKp44 have been shown to contain precursors of ILC1, ILC2, and ILC3. However, these ILCs have not been extensively characterized. We performed an unbiased hierarchical stochastic neighbor embedding (HSNE) analysis of the phenotype of peripheral blood CD117⁺ ILCs, which revealed the presence of three major subsets: the first expressed NKp46, the second expressed both NKp46 and CD56, and the third expressed KLRG1, but not NKp46 or CD56. Analysis of their cytokine production profiles and transcriptome revealed that NKp46⁺ ILCs predominantly develop into ILC3s; some of them can differentiate into ILC1/NK-like cells, but they are unable to develop into ILC2s. In contrast, KLRG1⁺ ILCs predominantly differentiate into ILC2s. Single-cell cultures demonstrate that KLRG1⁺ ILCs can also differentiate into other ILC subsets depending on the signals they receive. Epigenetic profiling of KLRG1⁺ ILCs is consistent with the broad differentiation potential of these cells.

Innate lymphoid cells (ILCs) are crucial for the immune surveillance at mucosal sites. ILCs coordinate early eradication of pathogens and contribute to tissue healing and remodeling, features that are dysfunctional in patients with cystic fibrosis (CF). The mechanisms by which ILCs contribute to CF-immunopathology are ill-defined. Here, we show that group 2 ILCs (ILC2s) transdifferentiated into IL-17-secreting cells in the presence of the epithelial-derived cytokines IL-1β, IL-23 and TGF-β. This conversion is abrogated by IL-4 or vitamin D3. IL-17 producing ILC2s induce IL-8 secretion by epithelial cells and their presence in nasal polyps of CF patients is associated with neutrophilia. Our data suggest that ILC2s undergo transdifferentiation in CF nasal polyps in response to local cytokines, which are induced by infectious agents.

Summary: Group 2 innate lymphoid cells (ILC2s) are the most well defined group of ILCs. ILC2 development is controlled by the GATA‐3 transcription factor and these cells produce archetypal type 2 cytokines, such as IL‐5 and IL‐13. These cytokines mediate parasite expulsion and tissue repair, but also contribute to type 2 inflammatory diseases, including allergy, asthma and chronic rhinosinusitis with nasal polyps. In response to tightly regulated local environmental cues ILCs can generate characteristics of other subtypes, a process known as plasticity. Recent advances in the ILC2 field has led to the discovery that ILC2s can promptly shift to functional IFN‐γ‐producing ILC1s or IL‐17‐producing ILC3s, depending on the cytokines and chemokines produced by antigen presenting cells or epithelial cells. Due to yet unknown triggers, this complex network of signals may become dysregulated. In this review, we will discuss general ILC characteristic, ILC2 development, plasticity, memory function, and implications in disease.

Innate lymphoid cells (ILC) represent a group of lymphocytes that lack specific antigen receptors and are relatively rare as compared to adaptive lymphocytes. ILCs play important roles in allergic and nonallergic inflammatory diseases due to their location at barrier surfaces within the airways, gut, and skin, and they respond to cytokines produced by activated cells in their local environment. Innate lymphoid cells contribute to the immune response by the release of cytokines and other mediators, forming a link between innate and adaptive immunity. In recent years, these cells have been extensively characterized and their role in animal models of disease has been investigated. Data to translate the relevance of ILCs in human pathology, and the potential role of ILCs in diagnosis, as biomarkers and/or as future treatment targets are also emerging. This review, produced by a task force of the Immunology Section of the European Academy of Allergy and Clinical Immunology (EAACI), encompassing clinicians and researchers, highlights the role of ILCs in human allergic and nonallergic diseases in the airways, gastrointestinal tract, and skin, with a focus on new insights into clinical implications, therapeutic options, and future research opportunities.

Innate lymphoid cells (ILCs) are important in the regulation of barrier homeostasis. These cells do not express T cell receptors but share many functional similarities with T helper cells and cytotoxic CD8+ T lymphocytes. ILCs are divided into three groups, namely group 1 ILCs, group 2 ILCs and group 3 ILCs, based on the transcription factors they depend on for their development and function, and the cytokines they produce. Emerging data indicate that ILCs not only have protective functions but can also have detrimental effects when dysregulated, leading to chronic inflammation and autoimmune diseases, including asthma, inflammatory bowel disease, graft-versus-host disease, psoriasis, rheumatoid arthritis and atopic dermatitis. Elucidation of the cytokine pathways involved in various autoimmune diseases - and the identification of ILCs as potent producers of these cytokines - points towards a potential role for these cellular players in the pathophysiology of these diseases. In this Review we discuss the current knowledge of the role of ILCs in the pathogenesis of rheumatic and other autoimmune diseases.

Background: Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model hampers mechanistic insight and the development of new therapeutics.Aim: We developed and characterized a robust, consistent, and reproducible mouse model of severe exacerbation of chronic allergic asthma.Methods: Chronic allergic airway inflammation was induced following a house dust mite (HDM) sensitization protocol. HDM‐sensitized mice and controls were infected with influenza virus A/X31 H3N2 and either or not treated with inhaled fluticasone propionate (FP), systemic corticosteroids (Pred), or anti‐IL‐5. Mice were killed at different time points after infection: Cellular accumulation and cytokines levels in the airways, PenH as a measure of airway hyper‐responsiveness (AHR), and lung histology and viral replication were assessed.Results: Infection with low‐dose A/X31 H3N2 led to prolonged deterioration of lung function, aggravated mucus production, peri‐vascular, peri‐bronchial, and allergic inflammation that was unresponsive to inhaled corticosteroids, but responsive to systemic corticosteroids. The exacerbation was preceded at 14 h after virus exposure by a marked innate, but no Th2 and Th1 response subsequently followed by enhanced numbers of eosinophils, neutrophils, dendritic, and T cells into the lung lumen, parenchyma, and draining lymph nodes in HDM‐sensitized mice. Anti‐IL‐5 treatment attenuated eosinophils and prevented the X31‐induced exacerbation.Conclusions: Together, these findings indicate that an early innate response that involves eosinophils underlies the exacerbation. This model recapitulates all major features of severe asthma exacerbations and can serve to discern driving mechanisms and promote the development of novel therapeutics.