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Review
. 2016 Oct 17;213(11):2229-2248.
doi: 10.1084/jem.20160525. Epub 2016 Oct 10.

Emerging concepts and future challenges in innate lymphoid cell biology

Elia D Tait Wojno  1   2 , David Artis  3   4   5
Affiliations
Review

Emerging concepts and future challenges in innate lymphoid cell biology

Elia D Tait Wojno et al. J Exp Med. .

Abstract

Innate lymphoid cells (ILCs) are innate immune cells that are ubiquitously distributed in lymphoid and nonlymphoid tissues and enriched at mucosal and barrier surfaces. Three major ILC subsets are recognized in mice and humans. Each of these subsets interacts with innate and adaptive immune cells and integrates cues from the epithelium, the microbiota, and pathogens to regulate inflammation, immunity, tissue repair, and metabolic homeostasis. Although intense study has elucidated many aspects of ILC development, phenotype, and function, numerous challenges remain in the field of ILC biology. In particular, recent work has highlighted key new questions regarding how these cells communicate with their environment and other cell types during health and disease. This review summarizes new findings in this rapidly developing field that showcase the critical role ILCs play in directing immune responses through their ability to interact with a variety of hematopoietic and nonhematopoietic cells. In addition, we define remaining challenges and emerging questions facing the field. Finally, this review discusses the potential application of basic studies of ILC biology to the development of new treatments for human patients with inflammatory and infectious diseases in which ILCs play a role.

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Figures

Figure 1.
Figure 1.
ILC3s promote GALT formation, inflammation, immunity, and homeostasis in the intestine. A progenitor that expresses multiple transcription factors, including PLZF and Id2, responds to IL-7 and differentiates into RORγt-expressing ILC3s (though notably CCR6-expressing/LTi cell progenitors do not express PLZF). Mature ILC3s then integrate multiple environmental cues that modulate their effector functions. These cells are activated by IL-23 produced by myeloid cells through expression of the IL-23R. They can also respond to signals from the microbiota and dietary factors, such as AhR ligands and vitamins. Together, these signals regulate the ability of ILC3s to produce cytokines such as lymphotoxin, IL-17, and IL-22. Three major ILC3 subsets exist, including the CCR6+NCR−T-bet− LTi and LTi-like cells, the CCR6−NCR−T-bet+ ILC3s, and the CCR6−NCR+T-bet+ ILC3s. ILC3-derived cytokines then promote GALT formation (LTi cells), regulate intestinal homeostasis and inflammation during IBD and in other contexts (CCR6−NCR+/−T-bet+ ILC3s), and contribute to protective immunity to intestinal pathogens (CCR6−NCR+/−T-bet+ ILC3s). Finally, LTi-like ILC3s express MHC class II, which allows them to interact with and delete commensal-specific CD4+ T cells to maintain tolerance of commensal bacterial species and intestinal homeostasis.
Figure 2.
Figure 2.
ILC2s influence inflammation, immunity, tissue repair, and homeostasis through interactions with hematopoietic and nonhematopoietic cells. ILC2s that express GATA3 differentiate from a progenitor cell that expresses a variety of transcription factors, including PLZF and Id2. These progenitors respond to IL-7 and other factors as they differentiate. Once mature, ILC2s sense multiple signals, including cytokines that can be derived from the epithelium, including IL-25, IL-33, and TSLP, and mast cell–derived eicosanoids such as PGD2 and others. Activated ILC2s produce type 2 cytokines, including IL-4, IL-5, IL-9, and IL-13. During N. brasiliensis infection, these cytokines are protective and elicit mucin production that induces helminth expulsion. These cytokines can also cause type 2 inflammation associated with allergic disease in multiple tissues. IL-9 feeds back in an autocrine loop to promote ILC2 survival during inflammation, and IL-4 produced by basophils also supports ILC2 population expansion (not depicted). The proinflammatory effects of ILC2s are balanced by their ability to promote homeostasis and tissue repair. In this context, type 2 cytokines derived from ILC2s support wound healing and maintain eosinophil (Eos) and alternatively activated macrophage (AAM) populations in adipose tissue, which, together with ILC2-derived met-enkephalin peptides, promote and support the lean state. Finally, activated ILC2s can produce growth factors that directly act on the epithelium to repair damaged tissues.
Figure 3.
Figure 3.
ILC1s express T-bet and IFN-γ and contribute to type 1 inflammation. T-bet–expressing ILC1s develop from a progenitor that expresses PLZF and Id2 and responds to IL-15. RORγt-expressing cells can also lose expression of RORγt and gain expression of T-bet in response to IL-12 signaling (ex-ILC3s). T-bet–expressing ILCs with a history of RORγt expression or T-bet+ ILC1s respond to IL-12 and IL-15 to produce IFN-γ that is protective during infection with pathogens such as C. difficile, T. gondii, and hepatitis B (not depicted: T-bet–expressing ILCs that currently or previously expressed RORγt are specifically important during infection with S. enterica as well, though these ILCs are more ILC3 like) and may contribute to inflammation and pathology in the intestine in the context of IBD.
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