Focus on Inflammatory Disease

Innate lymphoid cells in the initiation, regulation and resolution of inflammation

Journal name:
Nature Medicine
Year published:
Published online


A previously unappreciated cell type of the innate immune system, termed innate lymphoid cells (ILCs), has been characterized in mice and humans and found to influence the induction, regulation and resolution of inflammation. ILCs have an important role in these processes in mouse models of infection, inflammation and tissue repair. Further, disease-association studies in defined patient populations have identified significant alterations in ILC responses, suggesting a potential role for these cell populations in human health and disease. In this review we discuss the emerging family of ILCs, the role of ILCs in inflammation, and how current or novel therapeutic strategies could be used to selectively modulate ILC responses and limit chronic inflammatory diseases.

At a glance


  1. Development and heterogeneity of the ILC family.
    Figure 1: Development and heterogeneity of the ILC family.

    ILCs develop from distinct progenitors in the fetal liver or bone marrow. All ILCs develop from CLPs, which can differentiate into NKps or CHILPs. CHILPs can further differentiate into LTi cells through α4β7 integrin-expressing intermediate populations, or into other ILC populations through differentiation to a PLZF-dependent ILCp. Further sequential engagement of transcription factors, cytokines and microbial signals is critical for the development of three distinct groups of mature ILCs. ILC1s express T-bet, are responsive to IL-12, and produce IFN-γ. ILC2s highly express GATA3; are responsive to IL-25, IL-33 and TSLP; and produce IL-4, IL-5, IL-9, IL-13 and amphiregulin. ILC3s express RORγt, are responsive to IL-1β and IL-23, and produce IL-17 and/or IL-22.

  2. ILCs promote acute inflammation and innate immunity to pathogens.
    Figure 2: ILCs promote acute inflammation and innate immunity to pathogens.

    ILCs promote innate immune responses to a number of pathogens in the intestine. (a) ILC1s promote innate immunity to intracellular pathogens, such as T. gondii, by producing TNF and IFN-γ in response to DC-derived IL-12, and they subsequently promote recruitment of inflammatory myeloid cells. (b) After infection with the helminth parasites N. brasiliensis or T. muris, ILC2s produce IL-13 in response to epithelial cell–derived IL-25, IL-33 and TSLP, which increases smooth muscle contractility and mucus production from goblet cells. (c) ILC3s produce IL-17 and IL-22 in response to DC-derived IL-23 and IL-1β, which promotes innate immunity to fungi and extracellular bacteria, such as C. rodentium and C. albicans. IL-17 and IL-22 promote neutrophil recruitment to the intestine and the production of antimicrobial peptides from IECs.

  3. ILC2s and ILC3s promote the resolution of inflammation and tissue repair.
    Figure 3: ILC2s and ILC3s promote the resolution of inflammation and tissue repair.

    (a) After viral infection in the lung, airway epithelial cells are damaged and, in conjunction with resident myeloid cell populations, produce IL-33. ILC2s respond to IL-33 and produce amphiregulin, which promotes repair of the airway epithelium. (b) In lymphoid tissues, such as the spleen and thymus, stromal cell damage induced by viral infection or irradiation results in increased numbers of ILC3s and increased cytokine production, in response to DC-derived IL-23. ILC3s directly promote restoration of stromal cell compartments through production of LTα1β2 and IL-22, which increase the proliferation and survival of tissue resident stromal cells. (c) In the intestine, ILC3 responses can be limited by a regulatory loop whereby commensal bacteria induce IEC expression of IL-25, which acts on DCs to limit ILC3 cytokine responses in a contact-dependent manner. In contrast, upon chemical-, infection- or irradiation-induced damage of the intestine, ILC3s are activated by DC-derived IL-1β, IL-23, TL1A and RA. Activation of ILC3s induces IL-22 production that directly promotes mucus production and epithelial cell repair, in part by acting directly on intestinal stem cells or progenitors.

  4. ILCs can promote chronic inflammation.
    Figure 4: ILCs can promote chronic inflammation.

    (a) In response to infection or allergen exposure, ILC2 responses are elicited in the lung (and skin) by epithelial cell– and myeloid cell–derived IL-25, IL-33 and TSLP. Further, ILC2 responses can be enhanced by basophil-derived IL-4 or mast cell-derived PGD2. Activated ILC2s can subsequently promote chronic inflammation via IL-5–dependent eosinophil recruitment, IL-13–mediated contraction of smooth muscle cells, collagen deposition, and AAMac differentiation, or by MHCII-mediated enhancement of TH2 cell responses, resulting in allergy and fibrosis. (b) In patients with psoriasis and in mouse models of skin inflammation, ILC3 responses are increased, which can occur in response to DC-derived IL-23. ILC3s largely promote skin inflammation through production of IL-22 and IL-17. Further, ILC3s are increased in the bronchoalveolar lavage fluid of patients with asthma and in mouse models of obesity-induced asthma. In mice this occurs through activation of the NLRP3 inflammasome and macrophage (Mφ) production of IL-1β. IL-1β activates ILC3s to produce IL-17, which directly promotes airway inflammation and hyper-responsiveness. (c) In the intestine ILC3s can promote IL-22–dependent tumor growth, which is in part dependent upon DC-derived IL-23. Further, ILC3s can mediate tissue inflammation in the intestine in response to DC-derived IL-23 and IL-12. This may occur through production of IL-17 by ILC3s, production of IFN-γ following loss of RORγt in ILC3s and differentiation to ex-ILC3s, or direct activation of tissue-resident ILC1s.

  5. ILCs can prevent or limit chronic inflammation.
    Figure 5: ILCs can prevent or limit chronic inflammation.

    (a) In the intestine, ILC2s respond to epithelial cell-derived IL-33, IL-25 and vasoactive intestinal peptide (VIP) to promote IL-5– and IL-13–dependent recruitment of eosinophils and differentiation of AAMacs. This process also occurs in adipose tissue, although the sources of IL-25 or IL-33 are less well defined. Differentiation of AAMacs or direct stimulation of adipocytes with IL-13 or methionine-enkephalin peptides (Met-enk) can promote metabolic homeostasis through a process known as beiging in the adipocytes. (b) ILC3s can limit chronic inflammation by regulating innate and adaptive immune responses in the intestine. ILC3 responses are induced in response to myeloid cell– and DC-derived IL-1β and IL-23 after recognition of pathogenic or commensal microbes. Production of ILC3-derived LTα1β2 or LTα3 can promote IgA production by B cells indirectly by modulating stromal cell or DC responses. Production of ILC3-derived GM-CSF can influence myeloid cell homeostasis to subsequently promote Treg cell responses and tolerance to food antigens. ILC3-intrinsic MHCII can directly kill commensal bacteria-specific CD4+ T cells with the potential to cause intestinal inflammation. Production of IL-22 by ILC3s can promote antimicrobial peptide production by IECs to limit colonization with commensal bacteria, such as segmented filamentous bacteria (SFB), or it can regulate the anatomical localization of lymphoid tissue resident commensal bacteria. Further, ILC3-derived IL-22 can induce fucosylation of IECs to promote colonization with beneficial bacteria.


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  1. Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York, USA.

    • Gregory F Sonnenberg &
    • David Artis
  2. Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.

    • Gregory F Sonnenberg &
    • David Artis
  3. The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, New York, New York, USA.

    • Gregory F Sonnenberg &
    • David Artis

Competing financial interests

David Artis is a scientific advisor for Bio-Techne and Second Genome, although these programs are not referred to herein.

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