Group 2 Innate Lymphoid Cells in Health and Disease
Abstract
Group 2 innate lymphoid cells (ILC2s) play critical roles in anti-helminth immunity, airway epithelial repair, and metabolic homeostasis. Recently, these cells have also emerged as key players in the development of allergic inflammation at multiple barrier surfaces. ILC2s arise from common lymphoid progenitors in the bone marrow, are dependent on the transcription factors RORα, GATA3, and TCF-1, and produce the type 2 cytokines interleukin (IL)-4, IL-5, IL-9, and/or IL-13. The epithelial cell–derived cytokines IL-25, IL-33, and TSLP regulate the activation and effector functions of ILC2s, and recent studies suggest that their responsiveness to these cytokines and other factors may depend on their tissue environment. In this review, we focus on recent advances in our understanding of the various factors that regulate ILC2 function in the context of immunity, inflammation, and tissue repair across multiple organ systems.
Innate lymphoid cells (ILCs) are part of a family of innate immune cells that are heterogeneous in their expression of transcription factors and production of effector cytokines (Bjorkstrom et al. 2013; Spits et al. 2013). ILCs do not express cell lineage (Lin) markers associated with T cells, B cells, dendritic cells (DCs), macrophages, and granulocytes, but do express CD90 (Thy1 antigen), CD25 (interleukin [IL]-2Rα), and CD127 (IL-7Rα) (Spits et al. 2013). These cells are derived from a common lymphoid progenitor, and their development is dependent on the common γ-chain (γc or CD132), IL-7, Notch, and the transcription factor inhibitor of DNA binding 2 (Id2) (Yokota et al. 1999; Satoh-Takayama et al. 2010; Monticelli et al. 2011; Wong et al. 2012). More recent studies indicate that the majority of ILCs are also dependent on the transcriptional repressor PLZF and that all ILC subsets arise from a Lin Id2 CD127 CD25 α4β7 precursor (Constantinides et al. 2014; Klose et al. 2014). ILCs are currently categorized into three distinct populations based on their differential developmental requirements, expression of defined transcription factors, and their expression of cell surface markers and effector cytokines (Spits and Cupedo 2012; Fuchs and Colonna 2013; Kim et al. 2013b; Spits et al. 2013, Walker et al. 2013): group 1 ILCs (ILC1s) include classical NK cells and T-bet-dependent, IFN-γ-producing ILCs; RORα- (Halim et al. 2012b; Wong et al. 2012), GATA3- (Hoyler et al. 2012; Klein et al. 2013), and TCF-1-dependent (Yang et al. 2013) group 2 ILCs (ILC2s) produce IL-4, IL-5, IL-9, IL-13, and/or amphiregulin (Monticelli et al. 2011); and RORγt-dependent group 3 ILCs (ILC3s) produce IL-17A and/or IL-22 (Fig. 1) (Sonnenberg and Artis 2012). These ILC populations are functionally analogous to the previously described TH1, TH2, and TH17 CD4 T helper cell subsets, respectively. However, although ILCs exhibit shared functions with adaptive CD4 T cells, they are unique in that they respond to innate signals in the absence of antigen specificity, lack T-cell receptors, and have distinct phenotypic and functional profiles.
The innate lymphoid cell family. Innate lymphoid cells (ILCs) are a heterogeneous family of innate immune cells that arise from a common Id2-dependent lymphoid progenitor in the bone marrow. Group 1 ILCs (ILC1s) respond to IL-12 and IL-15, express the transcription factor T-bet, and produce tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ). Group 2 ILCs (ILC2s) respond to IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), express the transcription factor GATA3, and produce IL-4, IL-5, IL-9, IL-13, and amphiregulin (Areg). Group 3 ILCs (ILC3s) respond to IL-23 and IL-1β, express the transcription factor RORγt, and produce IL-17A and IL-22.
Different subsets of ILCs promote either tissue homeostasis or detrimental inflammatory processes at multiple epithelial barrier surfaces (Monticelli et al. 2011; Sonnenberg et al. 2012; Hepworth et al. 2013; Qiu et al. 2013). Further, these cells have been implicated in a variety of different disease states including allergy, autoimmunity, cancer, infection, and obesity (Sonnenberg and Artis 2012; Kim et al. 2013b; Molofsky et al. 2013; Nussbaum et al. 2013). The roles of the ILC1 and ILC3 subsets in various diseases have been covered elsewhere (Spits and Cupedo 2012; Fuchs and Colonna 2013; Sonnenberg 2013; Sonnenberg et al. 2013; Spits et al. 2013). Therefore, in this review, we will focus primarily on the emerging role of ILC2s in both health and disease across multiple organ systems. First, we will introduce ILC2s and the context in which these cells were originally identified. Second, we will give an overview of the factors that broadly regulate ILC2s and their known effector functions. Finally, we will discuss recent advances in our understanding of how ILC2s contribute to both homeostasis and inflammation in a tissue-specific and disease-oriented manner.
Footnotes
Editor: Ruslan M. Medzhitov
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