Airway innate lymphoid cells in the induction and regulation of allergy

Abstract

The recent discovery of innate lymphoid cells has revolutionized our understanding of the pathogenesis of immune diseases including allergy and asthma. Innate lymphoid cells (ILCs) are a heterogeneous collection of lymphocytes that lack antigen-specificity (non-T, non-B cells) and potently produce characteristic cytokines of T cell subsets (Th1, Th2, Th17). ILCs are divided into group 1 (ILC1s), group 2 (ILC2s), or group 3 (ILC3s). Similar to Th2 cells, ILC2s produce IL-4, IL-5, and IL-13, among others, and are present in increased numbers in samples from patients with many allergic disorders including asthma and chronic rhinosinusitis (CRS). Animal models have identified that ILC2s contribute to eosinophilic tissue infiltration, airway hyperresponsiveness, mucus production, as well as coordinate adaptive immune responses. Finally, recent studies support regulation of ILC2s by neuro-immune mechanisms as well as demonstrate a significant degree of plasticity between ILC subsets that may impact the immune responses in asthma and allergic airway diseases. Here, we review the current literature on ILC2s in human asthma and allergic airway diseases, as well as highlight some recent mechanistic insights into ILC2 function from in vitro studies and in vivo animal models.

Keywords: AERD; Asthma; Chronic rhinosinusitis; ILC2; Innate lymphoid cells.

Fig. 1

ILC2 contributions to airway remodeling in asthma and normal tissue repair responses. Activated ILC2s produce IL-13 that promotes subepithelial fibrosis, airway hyper-responsiveness (AHR), smooth muscle increases, and epithelial mucus production (along with IL-9). Further, ILC2s produce IL-5 which induces proliferation of eosinophils that express the pro-fibrotic growth factor TGF-β. In the normal airway, amphiregulin production by ILC2s may maintain normal tissue homeostasis and repair lung structures after viral infections.

Fig. 2

Activated ILC2 responses and plasticity in allergic airway diseases. TSLP, IL-33, and IL-25 are induced by epithelial damage after exposure to allergens, specific viruses or irritants. These cytokines, as well as cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2) induce Th2 cytokine production from ILC2s. IL-5 promotes tissue eosinophilia, IL-13 induces AHR, mucus production and immune cell recruitment, and IL-9 promotes mast cell accumulation and mucus production (not shown). CysLTs specifically induce ILC2 IL-4 production that can promote Th2 cell differentiation and IgE class switching from B cells. ILC2s can also be converted to ILC1-like cells by IL-1b, IL-12 and IL-18 leading to production of IFNγ and TNFα. Sustained production of IL-33, notch ligands, and CysLTs also induce IL-17 from ILC2s. IL-1b may also directly promote ILC3 generation in obesity. Th1/Th17 cytokines may promote neutrophilic airway disease as well as AHR in some circumstances. Inhibitory pathways not shown, and reviewed elsewhere.