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Regulatory roles of dermal type 2 innate lymphoid cells

Cellular & Molecular Immunology volume 10, pages 453–455 (2013)Cite this article

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Type 2 immune immunity evolved a unique system to protect against noxious xenobiotics at the epithelial barrier.1 Recently, epithelial cell-derived cytokines IL-25, IL-33 and TSLP have been shown to be critical in producing Th2 cytokines, including IL-4, IL-5, IL-9 and IL-13, by type 2 innate lymphoid cells (ILC2s) as well as Th2 cells. Even though numerous studies have demonstrated that ILC2s are able to initiate a variety of reactions associated with type 2 immune responses independently of Th2 cells, little is known about whether they control the activity of other immune cells. In a paper published in Nature Immunology, Roediger et al.2 have demonstrated that ILC2s have two different mechanisms that could be crucial for maintaining skin homeostasis under steady state conditions and mediating skin inflammation.

Innate lymphoid cells are differentiated from Id2-expressing common lymphoid cells, but the specification of subsets is determined by different transcription factors.3 Two transcript factors GATA-3 and RORα are required for ILC2 differentiation.3 ILC2s are heterogeneous in terms of their phenotypes and tissue distribution. However, their effector functions are commonly mediated through Th2 cytokines and other soluble factors. Given the intrinsic properties of ILC2s and their location in lymphoid organs and at mucosal sites, ILC2s are considered to be a first line of defense against noxious allergens and parasitic infections. However, in line with Th2 immunity that plays an essential role in tissue repair in organs that experience tissue damage resulting from overly exuberant immune responses, ILC2s have been found to participate in lung repair after infection with influenza virus.4 In addition, ILC2s maintain visceral adipose tissue eosinophils and M2 macrophages to regulate metabolic homeostasis.5 Roediger et al.2 have identified a unique dermal ILC2s that express CD103 (αEβ7 integrin expressed by skin-resident T cells) and constitutively express IL-13. Using reporter mice, they have convincingly shown that ILC2s patrol the skin under the steady state and interact with skin-resident mast cells. In in vitro experiments, IL-13 has been shown to inhibit the ability of primed mast cells to product IL-6 and TNF upon exposure to antigen. On the other hand, another independent research group has demonstrated that skin-resident ILC2s are indispensible for atopic dermatitis (AD)-like disease induced by the vitamin D3 analog MC903.6 This chemical is a potent inducer of TSLP (but not IL-25 and IL-33) production by keratinocytes. Which cytokine is produced among IL-25, IL-33 and TSLP at mucosal barriers seems to be determined by types of allergens, parasites and other injury inducers, and responding parenchymal and stromal cells. The vitamin D3 analog MC903 has been shown to result in AD-like disease by inducing TSLP production by skin keratinocytes.7 One important finding by Roediger et al.2 is that treatment with complexes of IL-2 and anti-IL-2 monoclonal antibody (potently stimulate the IL-2 receptor) in Rag1−/− mice elicits AD-like disease with characteristics of eosinphil infiltrates and activated mast cells through the expansion of IL-5-producing dermal ILC2s. It remains to be determined whether IL-2 produced by allergen-primed Th2 T cells can participate in the expansion of ILC2s during allergic responses in T cell-replete mice. Although IL-2 can potentiate the proliferation and activation of ILC2s in IL-25- and/or IL-33-rich milieu, IL-2 may directly act on ILC2s in such conditions that these acute phase cytokines are no longer present in inflamed sites. There is compelling evidence that during papain-induced lung inflammation, IL-2 from adaptive immune cells elicits a transit production of IL-9 by ILC2s and IL-9 subsequently results in their production of IL-5 and IL-13 in an autocrine fashion.8 This observation suggest that once adaptive immunity is initiated, it can recruit all types of innate immune cells available, including ILC2s, to reinforce allergic responses.9

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Acknowledgements

Byungsuk Kwon's laboratory is supported by a grant (BRL 2009-0087350) from the National Research Foundation of Korea.

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  1. School of Biological Sciences, University of Ulsan, Ulsan, Korea

    Byungsuk Kwon

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Kwon, B. Regulatory roles of dermal type 2 innate lymphoid cells. Cell Mol Immunol 10, 453–455 (2013). https://doi.org/10.1038/cmi.2013.34

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