Mechanisms of allergy and clinical immunology
Innate IL-13–producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity

https://doi.org/10.1016/j.jaci.2011.09.041Get rights and content

Background

IL-4, IL-5, and IL-13 are thought to be central to the allergic asthmatic response. Previous work supposed that the essential source of these cytokines was CD4+ TH2 cells. However, more recent studies have suggested that other innate production of type 2 cytokines might be as important.

Objectives

Nuocytes are a novel population of IL-13–producing innate cells, which are critical for protective immunity in Nippostrongylus brasiliensis infection. Given this, we investigated the potential existence and functional importance of nuocytes in experimental allergic asthma.

Methods

We generated Il4+/eGFPIl13+/Tomato dual-reporter mice to study cytokine-producing cells during allergic inflammation. We adoptively transferred innate IL-13–producing cells to investigate their role in airways hyperreactivity (AHR).

Results

We show that allergen-induced nuocytes infiltrate the lung and are a major innate source of IL-13. CD4+ T cells in the lung almost exclusively express only IL-13, whereas IL-4–producing T cells were restricted to the draining lymph nodes. Intranasal administration of IL-25 or IL-33 induced IL-13–producing nuocytes in the BAL fluid. Strikingly, adoptive transfer of wild-type nuocytes, but not Il13−/− nuocytes, into Il13−/− mice, which are normally resistant to IL-25–induced AHR, restored airways resistance and lung cell infiltration.

Conclusions

These findings identify nuocytes as a novel cell type in allergic lung inflammation and an innate source of IL-13 that can directly induce AHR in the absence of IL-13–producing CD4+ T cells. These data highlight nuocytes as an important new consideration in the development of future allergic asthma therapy.

Section snippets

Mice

Il13 was targeted in murine embryonic stem cells by using a recombineering strategy.17 A 5.9-kb genomic DNA fragment spanning exons 1 to 4 was amplified by means of PCR with primers ASEQ3819 (NotI site) and ASEQ3820 (SpeI site) and cloned into the plasmid pl2XR. The fluorescent tandem (td)Tomato cassette was recombineered at the start codon of Il13. The screening probe was amplified by means of PCR from murine genomic DNA using primers ASEQ3058 AGTCACGAGCCAGACCATTC and ASEQ3059

Nuocytes arise during allergic lung inflammation

Allergic lung inflammation occurs as a direct consequence of IL-4, IL-5, and IL-13 cytokine release by immune cells, such as TH2 cells, mast cells, basophils, and eosinophils. Mice were sensitized and challenged with OVA by using either a short 12-day model or a longer 25-day model to determine whether nuocytes form part of this infiltrating cell milieu.

In both protocols side scatter–low cells were found to infiltrate the lung after OVA treatment, and of these cells, around 15% to 20% were

Discussion

Nuocytes are important new innate cells that produce IL-5 and IL-13 (and low levels of IL-4) in response to IL-25 and IL-33, factors that can be produced by airways epithelial cells,9, 29 although their triggers remain elusive. Induction of nuocytes has been shown to be necessary for initiating type 2 responses during N brasiliensis infection.13 Significantly, this opens the possibility that nuocytes and other innate populations like them14, 15 represent a new piece to the type 2 puzzle located

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    J.L.B. and S.H.W. were supported by a grant from Centocor, and A.N.J.M. was supported by grants from the American Asthma Federation (no. 10-0078) and Asthma UK (no. 07/001).

    Disclosure of potential conflict of interest: J. L. Barlow has received research support from Centocor. A. N. J. McKenzie has received research support from Centocor and the American Asthma Foundation. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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