Pulmonary group 2 innate lymphoid cells: surprises and challenges

Abstract

Group 2 innate lymphoid cells (ILC2s) are a recently described subset of innate lymphocytes with important immune and homeostatic functions at multiple tissue sites, especially the lung. These cells expand locally after birth and during postnatal lung maturation and are present in the lung and other peripheral organs. They are modified by a variety of processes and mediate inflammatory responses to respiratory pathogens, inhaled allergens and noxious particles. Here, we review the emerging roles of ILC2s in pulmonary homeostasis and discuss recent and surprising advances in our understanding of how hormones, age, neurotransmitters, environmental challenges, and infection influence ILC2s. We also review how these responses may underpin the development, progression and severity of pulmonary inflammation and chronic lung diseases and highlight some of the remaining challenges for ILC2 biology.

Figure 1. ILCs in respiratory diseases

A. In asthma ILC2 development and activity is driven by eicosanoids, prostaglandin D2 (PGD2) and leukotrienes from mast cells, macrophages and eosinophils, as well as innate type-2 cytokines IL-33, -25, TSLP and neuromedin U (NMU). This is accompanied by increases in ILC2 markers such as Arginagse-1 and the neuropeptide receptor Nmur1. Activated ILC2s release IL-5 and -13 that activate DCs and Th2 cells to reinforce type-2 immunity and asthma pathogenesis by inducing eosinophilic airway inflammation, mucus hypersecretion, airway remodeling and airway hyperresponsiveness (AHR, wheezing). These responses are opposed by lipoxin A4 and E-cadherin actions released from neutrophils, epithelial cells and macrophages, and by increases in type I IFNs, IFN-γ and IL-27 that are induced by typical viral infections. B. In COPD cigarette smoke and likely air pollution induce the increased expression of IL-33 that is released upon viral infection and exacerbates the underlying disease. However, acute smoke exposure reduces IL-5 and -13 responses and ST2 expression on ILC2s. ST2 inhibition suppresses virus-induced exacerbation of acute cigarette smoke-driven inflammation, IL-33 enhances macrophage and NK cell killing of virus, and ILC2s and IL-33 promote airway fibrosis. C. Helminth infections induce granulomas and fibrosis that are dependent on IL-33, -25, TSLP, IL-17 and IL-13⁺ ILC2s. Combined targeting of IL-33, -25 and TSLP suppressed type-2 driven inflammation, IL-13+ ILC2s, airway remodelling and fibrosis. IL-5⁺ and IL13⁺ ILC2s induce macrophage, eosinophil and mucus activity that destroy and clear helmniths but eosinophils promote fibrosis and allergy. D. In early life, rhinovirus (RV) and respiratory syncytial virus (RSV) induce IL-33, -25, TSLP and IL-13⁺ ILC2s, airway eosinophilia, mucus hypersecretion and AHR and predispose to the development of asthma. IFN-γ suppresses ILC2s, but infection reduces IFN-γ, IL-12 and TNF expression. E. Asthma and COPD patients are more susceptible to bacterial and viral infections such as with influenza A virus (IAV), which induce the accumulation of ILC2s in the lung that are tissue protective. They also typically induce type-1 responses that restrict ILC2s but also type-2 responses that are responsible for tissue protection but IL-13 and -33 contribute to asthma exacerbations. IAV infection induces AHR independently of Th2 cells in an IL-13/-33/ST2/ILC2-mediated axis. IAV infection induces IL-33 production from alveolar macrophages and NKT cells that increase ILC2s, and causes transient IL-5 production, and the influx of c-kit⁺ ST2⁺ ILC2s and associated eosinophils that exacerbate asthma. In COPD ILC2s are plastic and upon IAV infection acquire an ILC1 phenotype, with reduced GATA-3 expression and produce IFN-γ, IL-12 and -18. These cells reinforce virus-induced inflammation and exacerbations.