IL-1\u03b2, IL-23, and TGF-\u03b2 drive plasticity of human ILC2s towards IL-17-producing ILCs in nasal inflammation

Maho Nagasawa,Balthasar A Heesters,Korneliusz Golebski,Chantal M A Kradolfer,Wytske J Fokkens,Sven Seys,Hajar Aglmous,Sophie Van Tol,Xavier R Ros,Suzanne M Bal,Hergen Spits,P W Hellings,Cornelis M Van Drunen,Medya M Shikhagaie

doi:10.1038/s41467-019-09883-7

Maho Nagasawa, Balthasar A Heesters + Show 12 more

Open Access

https://doi.org/10.1038/s41467-019-09883-7

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Abstract

Innate lymphoid cells (ILCs) are crucial for the immune surveillance at mucosal sites. ILCs coordinate early eradication of pathogens and contribute to tissue healing and remodeling, features that are dysfunctional in patients with cystic fibrosis (CF). The mechanisms by which ILCs contribute to CF-immunopathology are ill-defined. Here, we show that group 2 ILCs (ILC2s) transdifferentiated into IL-17-secreting cells in the presence of the epithelial-derived cytokines IL-1β, IL-23 and TGF-β. This conversion is abrogated by IL-4 or vitamin D3. IL-17 producing ILC2s induce IL-8 secretion by epithelial cells and their presence in nasal polyps of CF patients is associated with neutrophilia. Our data suggest that ILC2s undergo transdifferentiation in CF nasal polyps in response to local cytokines, which are induced by infectious agents.

Highlights

Innate lymphoid cells (ILCs) are crucial for the immune surveillance at mucosal sites
To evaluate the role of ILCs in the sinonasal inflammation in cystic fibrosis (CF) patients, we examined the composition of ILC subsets in NP of these patients as compared with those from chronic rhinosinusitis with nasal polyps (CRSwNP) patients and healthy nasal tissue
We cannot exclude that Th17 cells and other cells can be a source of IL-17 in these patients, this indicates that NKp44− ILC3s are at least partly responsible for the IL-17 production in NP of CF patients

Summary

Introduction

Innate lymphoid cells (ILCs) are crucial for the immune surveillance at mucosal sites. IL-17 producing ILC2s induce IL-8 secretion by epithelial cells and their presence in nasal polyps of CF patients is associated with neutrophilia. The respiratory tract of most patients with CF becomes infected with opportunistic bacteria, most importantly Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA)[4] This eventually results in lung damage and loss of pulmonary function, the major cause of morbidity and mortality in CF disease[5]. ILC3s and ILC2s can transdifferentiate into IFN-γproducing ILC1s in the presence of IL-12 and ILC1s can shift into ILC3s in response to IL-23, IL-1β, and retinoic acid[20,21,22] These transdifferentiation processes result in increased IFN-γ producing ILC1-like cells as observed in inflamed tissue of Crohn’s patients and in lung tissue from individuals with severe COPD22,23

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