Group 2 innate lymphoid cells display ILC3-like functional plasticity in asthmatics and non-human primates

RATIONALE: The underlying mechanisms that drive neutrophilic asthma are poorly understood. Recently group 2 innate lymphoid cells (ILC2s) have been described as an important cellular player in severe asthma. Our laboratory has shown that following ozone exposure in mice, ILC2s acquire an ILC3-like phenotype and produce IL-17A and IL-22. We hypothesized that ILC2s display ILC3-like functionality in asthma and produce IL-17A and IL-22 to promote neutrophilia.

METHODS: To study cytokine production in ILC2s, we recruited severe asthma patients from the UC Davis Asthma Network Clinic and acquired non-human primates (NHP; Rhesus macaque). Human and NHP subjects underwent lung function measurements. Human subjects were segregated into severe asthma and control groups, while NHP were segregated into AHR+ and AHR- groups. ILC2 and ILC3 numbers were assessed via flow cytometry of PBMCs. Cytokine production was studied after restimulation and intracellular staining (severe asthma patients) or qPCR (non-human primates) of ILC2s isolated via FACS.

RESULTS: Severe asthma patients and AHR+ NHP had increased numbers of circulating ILC2s compared to healthy controls or AHR- NHP, respectively. ILC2s from severe asthma patients had constitutive, increased expression of IL-13 and IL-17A compared to healthy controls, however upon restimulation IL-13 and IL-17A production was reduced and IL-22 production increased. ILC2s isolated from AHR+ NHP displayed increased IL-4, IL-22, and GATA3 gene expression compared to AHR- NHP.

CONCLUSIONS: We propose that ILC2 displaying ILC3-like functionality are potentially important in neutrophilic asthma, and how IL-17A and IL-22 produced in conjunction with IL-5 and IL-13 might impact inflammation will be important for future studies.