Type 2 innate lymphoid cells (ILC2s) have recently been identified in human nasal polyps, but whether numbers of ILC2s differ by polyp endotype or are influenced by corticosteroid use is unknown. Here, we show that eosinophilic nasal polyps contained double the number of ILC2s vs. non-eosinophilic polyps. Polyp ILC2s were also reduced by 50% in patients treated with systemic corticosteroids. Further, using a fungal allergen challenge mouse model, we detected greatly reduced Th2 cytokine-producing and Ki-67+ proliferating lung ILC2s in mice receiving dexamethasone. Finally, ILC2 Annexin V staining revealed extensive apoptosis after corticosteroid treatment in vivo and in vitro. Thus, ILC2s are elevated in the eosinophilic nasal polyp endotype and systemic corticosteroid treatment correlated with reduced polyp ILC2s. Finally, allergen-challenged mice showed reduced ILC2s and increased ILC2 apoptosis after corticosteroid treatment suggesting that ILC2 may be responsive to corticosteroids in eosinophilic respiratory disease.

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SHORT SUMMARY Type 2 innate lymphoid cells (ILC2) produce high levels of Th2 cytokines. Our study demonstrates that cat allergen challenge in allergic rhinitis subjects rapidly induces increased peripheral blood ILC2.

Asthma is a complex disease promoted by dysregulated immunity and the presence of many cytokine and lipid mediators. Despite this, there is a paucity of data demonstrating the combined effects of multiple mediators in asthma pathogenesis. Group 2 innate lymphoid cells (ILC2s) have recently been shown to play important roles in the initiation of allergic inflammation, however it is unclear whether lipid mediators such as cysteinyl leukotrienes (CysLTs) that are present in asthma could further amplify the effects of IL-33 on ILC2 activation and lung inflammation. Here we show that airway challenges with the parent CysLT leukotriene C4 (LTC4) given in combination with Iow dose IL-33 to naïve WT mice led to synergistic increases in airway Th2 cytokines, eosinophilia and peribronchial inflammation compared with IL-33 alone. Further, the numbers of proliferating and cytokine-producing lung ILC2s were increased after challenge with both LTC4 and IL-33. Levels of CysLT1R, CysLT2R and candidate LTE4 receptor P2Y12 mRNAs were increased in ILC2s. The synergistic effect of LTC4 with IL-33 was completely dependent upon CysLT1R as CysLT1R−/−, but not CysLT2R−/− mice, had abrogated responses. Further, CysLTs directly potentiated IL-5 and IL-13 production from purified ILC2s stimulated with IL-33 and resulted in NFAT1 nuclear translocation. Finally, CysLT1R−/− mice had reduced lung eosinophils and ILC2 responses after exposure to the fungal allergen Alternaria alternata. Thus, CysLT1R promotes LTC4- and Alternaria-induced ILC2 activation and lung inflammation. These findings suggest that multiple pathways likely exist in asthma to activate ILC2s and propagate inflammatory responses.

SHORT SUMMARY Group 2 innate lymphoid cells (ILC2s) produce high levels of IL-5 and IL-13, both of which are important pathogenic mediators in eosinophilic esophagitis (EoE). ILC2s have not been previously described in EoE. Our study demonstrates the novel finding that ILC2s are increased in esophageal biopsies from EoE patients with active disease compared with inactive EoE and non-diseased controls, implicating these cells in EoE pathogenesis.