Group 2 innate lymphoid cells in disease

Abstract

Group 2 innate lymphoid cells (ILC2) are now recognized as an important innate source of type-2 effector cytokines. Although initially associated with mucosal tissues, it is clear that ILC2 are present in diverse anatomical locations. The function of ILC2 at these sites is equally varied, and although ILC2 represent a relatively minor population, they are fundamentally important regulators of innate and adaptive immune processes. As such, there is much interest to understand the role of ILC2 in diseases with a type-2 inflammatory component. This review explores the known roles of ILC2 in disease, and the diseases that show associations or other strong evidence for the involvement of ILC2.

Keywords: ILC2; allergies; innate immunity; type-2 inflammation.

Fig. 1.

Regulation of ILC2 by soluble-molecules and cell-to-cell receptors. ILC2 are primarily regulated by the ‘alarmins’ IL-25, IL-33 and TSLP but are also influenced strongly by other cytokines, lipid mediators, or cell-surface molecules. TSLP, thymic stromal lymphopoietin; DR3, death receptor 3—tumor necrosis factor receptor superfamily member 25; LTD ₂ , Leukotriene D ₂ ; LXA ₄ , Lipoxin A ₄ ; PGD ₂ , prostaglandin D ₂ .

Fig. 2.

Effector functions of ILC2-derived cytokines. Activated ILC2 are a source of effector cytokines, which are important regulators of inflammation and homeostasis. ILC2 can also produce IL-4 when stimulated with prostaglandin D ₂ . AAM, alternatively activated macrophage; Areg, amphiregulin; DC, dendritic cell; Eosin., eosinophil.

Fig. 3.

ILC2 interaction with the adaptive immune system in allergic lung inflammation. Allergen exposure to the airways results in a rapid release of alarmins, including IL-33, which activate lung-resident ILC2. DCs are also activated and require ILC2-derived IL-13 to efficiently traffic to the draining LN, where they cross-present antigen to naive CD4 ⁺ T cells, resulting in T _h2 cell priming. Antigen-specific T _h2 cells exit the LN and can be (hypothetically) locally activated by MHCII ⁺ ILC2 presenting allergen-peptide, resulting in IL-2 production and release. IL-2 and IL-33 potently synergize to further activate ILC2. DC, dendritic cell; LN, lymph node.