CCR10⁺ILC2s with ILC1‐like properties exhibit a protective function in severe allergic asthma

Abstract

Background:We previously showed that patients with severe allergic asthma have high numbers of circulating ILC2s expressing CCR10. Method:Herein, CCR10 + ILC2s were further analyzed in the blood of healthy individuals or patients with allergic and non−allergic asthma. Characteristics of human CCR10 + and CCR10 − ILC2s were assessed by flow cytometry as well as single-cell multiplex RT-qPCR. The role of CCR10 + ILC2s in asthma pathophysiology was studied in allergen-treated mice.Results: When compared to healthy controls, CCR10 + ILC2s are enriched in the blood of both allergic and non-allergic severe asthmatic patients, and these cells are recruited to the lungs. Plasma concentrations of the CCR10 ligand CCL27 are significantly increased in severe asthmatics when compared to non-asthmatic patients.CCR10 + ILC2s secrete little T H 2 cytokines, but exhibit ILC1-like properties, including a capacity to produce IFN-γ. Also, single-cell analysis reveals that the CCR10 + ILC2 subset is enriched in cells expressing amphiregulin. CCR10 + ILC2 depletion, as well as blocking of IFN-γ activity, exacerbates airway hyperreactivity in allergen-challenged mice, providing evidence for a protective role of these cells in allergic inflammation. Conclusions:Frequencies of circulating CCR10 + ILC2s and CCL27 plasma concentrations represent candidate markers of asthma severity. The characterization of CCR10 + ILC2s in human samples and in mouse asthma models suggests that these cells downregulate allergic inflammation through IFN-γ production.

Functional Contribution and Targeted Migration of Group-2 Innate Lymphoid Cells in Inflammatory Lung Diseases: Being at the Right Place at the Right Time

“…Although classically described as a skin homing receptor, the chemokine receptor CCR10 was found to be expressed on the surface of more than one third of pulmonary ILC2s in noninflamed human lungs and, moreover, asthma patients could be characterized by a markedly increased frequency of CCR10 + ILC2s and elevated levels of CCL27 in the peripheral blood, implicating a potential impact of CCR10 and its ligands CCL27 on the inflammation-dependent enrichment of pulmonary ILC2 pools. In accordance with this hypothesis, in vivo blockade of CCR10 ligands indeed abolished the pulmonary presence of CCR10 + ILC2s in allergen-exposed mice (141). Taking into account the described capacity of CCR10 + ILC2s to ameliorate allergic lung inflammation, the CCR10-mediated recruitment of pulmonary ILC2s might be of particular relevance for maintenance or restoration of the balance between the pro-inflammatory effects of lung ILC2s and their capacity to enhance resolution of inflammation.…”

“…Further following this hypothetical idea, CCR10 + ILC2s can be considered as interesting candidates for cellular therapy of patients suffering from severe asthma. Based on the combined interpretation of descriptive human data acquired in blood-and lung tissuederived ILC2s and functional murine analyses in an experimental model of intranasal allergen-challenge, a suppressive function of lung infiltrating CCR10 + ILC2s on allergic airway inflammation has been strongly suggested, which was obviously due to ILC1-like properties of this specific ILC2 subfraction and their increased capacity for IFNg secretion (141). Provided that it will be feasible to ex vivo expand CCR10 + ILC2s under the stable maintenance of their functional properties, it can thus be assumed that asthma patients might benefit from the adoptive transfer and the subsequent intended pulmonary enrichment of these suppressive ILC2s.…”

The Cytokines of Asthma

“…However, ILC2s potentially contribute more to lung repair (Figure 2A and 2B) (Drake et al, 2014;Li et al, 2016;Mohapatra et al, 2016;Oeser et al, 2015). Single-cell RNA-seq studies on the heterogeneity of ILC2s that are now emerging could potentially shed light on the unique tissue-specific functions of ILC2s, including beneficial effects on lung repair, through secretion of amphiregulin (Beuraud et al, 2018;Ricardo-Gonzalez et al, 2018;Wallrapp et al, 2017).…”

Role of IL‐25, IL‐33, and TSLP in triggering united airway diseases toward type 2 inflammation

“…IL‐33–induced type 2 responses can be amplified by the co‐stimulatory molecule OX40L on DCs, upregulated by IL‐33 53 . In addition, the recruitment of ILC2s induced by vascular cell adhesion molecule 1 (VCAM‐1) in the endothelial cells of the lung depends on the receptor for advanced glycation end products (RAGE) 54‐56 . Stimulations of mice with recombinant IL‐33 resulted in blood eosinophilia, and increased serum levels of IgE, IgA, IL‐5, IL‐13, and splenomegaly, while anti–IL‐33 treatment significantly reduced nose‐scratching events, ameliorated nasal cavity eosinophilia, and downregulated serum IgE levels in the murine model of AR 57 …”