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Innate lymphoid cells — how did we miss them?

Key Points

  • Innate lymphoid cells (ILCs) are newly identified members of the lymphoid lineage with emerging roles in mediating immune responses and in regulating tissue homeostasis and inflammation.

  • The existence of different ILC populations that can rapidly secrete immunoregulatory cytokines suggests that these cells may have evolved to provide immunity to infections. Indeed, it is notable that ILC subsets seem to be particularly prevalent at mucosal surfaces, which are constantly exposed to infectious agents in the external environment.

  • The group 1 ILC lineage comprises ILCs such as natural killer (NK) cells that produce type 1 cytokines, notably interferon-γ and tumour necrosis factor. Other group 1 ILCs have been reported, mainly in vitro, and their physiological roles remain to be defined.

  • The group 2 ILC population comprises ILC2s, which express interleukin-5 (IL-5) and IL-13 and require GATA-binding protein 3 (GATA3) and retinoic acid receptor-related orphan receptor-α (RORα) for their development. They have crucial roles in protective type 2 immunity to helminth infection. Furthermore, although T helper 2 cells are a major source of type 2 cytokines during allergic asthma, ILC2s also contribute to disease pathology.

  • ILC3s were first defined as intestinal lymphoid cells that express the NK cell activating receptor NKp46, but otherwise bear little functional resemblance to conventional NK cells, and require RORγ for their development. They express IL-17A and IL-22.

  • Recent studies have also implicated ILC3s in the development of inflammatory bowel disease. Studies in Rag2−/− mice demonstrated that, in the early phase of Citrobacter rodentium infection, IL-22 is produced from an innate cell source.

  • Lymphoid tissue-inducer (LTi) cells are an ILC subset that appears to be closely related to ILC3s, but their exact relationship remains controversial. Together, LTi cells and ILC3s have been classified as group 3 ILCs.

Abstract

Innate lymphoid cells (ILCs) are newly identified members of the lymphoid lineage that have emerging roles in mediating immune responses and in regulating tissue homeostasis and inflammation. Here, we review the developmental relationships between the various ILC lineages that have been identified to date and summarize their functions in protective immunity to infection and their pathological roles in allergic and autoimmune diseases.

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Figure 1: ILC subsets, functions and disease associations.
Figure 2: A model for ILC development.
Figure 3: Schematic of the roles for ILCs in intestinal immune function.
Figure 4: Comparison of T helper cell and ILC subsets.

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Acknowledgements

The authors would like to thank S. Bell, C. Oliphant and S. Scanlon for critical appraisal of the manuscript. J.A.W. and A.N.J.M. are supported by the American Asthma Foundation.

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Glossary

Type 1 immune responses

Type 1 immune responses are characterized by the production of cytokines such as interferon-γ interleukin-2, tumour necrosis factor and lymphotoxin-α by various immune cells, including T helper 1 cells, neutrophils, macrophages and NK cells. Such responses protect against intracellular pathogens and are also implicated in several autoimmune diseases.

Type 2 immune responses

Type 2 immune responses are characterized by the secretion of cytokines such as interleukin-4 (IL-4), IL-5, IL-9 and IL-13 by various immune cells, including T helper 2 cells, eosinophils, basophils, mast cells and ILC2s. Such responses are required for controlling extracellular parasite infections, but they are also responsible for the immunopathology that develops in patients with allergy and asthma.

TH17 cells

A subset of CD4+ T helper cells that secrete predominantly the pro-inflammatory cytokine interleukin-17A and have been implicated in the pathogenesis of many chronic inflammatory disorders.

T follicular helper cells

(TFH cells). A subset of CD4+ helper T cells that interact with B cells within germinal centres to provide co-stimulatory signals and regulate the development of antigen-specific B cell immune responses.

OP9 cells

A bone marrow-derived stromal cell line used to support haematopoietic stem cells and common lymphoid progenitor cells during in vitro culture. The OP9–DL1 variation of this cell line ectopically expresses the Notch ligand Delta-like 1, which promotes the differentiation of T cells.

Common lymphoid progenitor

(CLP). CLPs are the earliest progenitors of the lymphoid cell lineages, which include B cells, T cells, NK cells and the newly described innate lymphoid cells. Bone marrow CLPs are defined by their expression of the IL-7 receptor, FMS-related tyrosine kinase 3 (FLT3) and KIT, and the absence of all conventional lineage markers.

Notch signalling

The Notch signalling pathway regulates cellular differentiation in various tissues and at various stages of development. During lymphopoiesis, signals through the Notch receptor modify gene expression patterns and have crucial roles in the development of T cells and the inhibition of B cell differentiation. In mammals, there are four Notch receptors, which bind to ligands of the Delta family (Delta-like 1, Delta-like 3 and Delta-like 4) and the jagged family (jagged 1 and jagged 2), which are typically expressed on stromal cells.

Aryl hydrocarbon receptor

(AHR). AHR is a cytosolic, ligand-dependent transcription factor that translocates to the nucleus following the binding of specific ligands, which include dietary and microbial metabolites. AHR participates in the differentiation of regulatory T cells, TH17 cells and intraepithelial intestinal γδ T cells, and it is required for the secretion of IL-22 by TH17 cells. More recently, AHR has been shown to have crucial roles in the development and function of LTi cells and ILC3s.

Forkhead box N1

(FOXN1). A winged-helix transcription factor that is thought to regulate keratin gene expression. Mutations in the Foxn1 gene result in a hairless ('nude') phenotype and athymia.

REG family of C-type lectins

Members of the REG3 subgroup of the C-type lectin family are antimicrobial peptides that interact with the peptidoglycans present on the surface of Gram-positive bacteria. They can be released into the intestinal lumen from multiple epithelial cell lineages.

Amphiregulin

A member of the epidermal growth factor family that drives the proliferation of epithelial cells and fibroblasts to promote tissue repair and remodelling in response to epithelial injury.

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Walker, J., Barlow, J. & McKenzie, A. Innate lymphoid cells — how did we miss them?. Nat Rev Immunol 13, 75–87 (2013). https://doi.org/10.1038/nri3349

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