IL-33 induced gene expression in activated Th2 effector cells is dependent on IL-1RL1 haplotype and disease status

BackgroundIL-33 can activate Th2 cells after binding to the IL-1RL1/IL-1RAcP receptor. However, it is unknown whether disease or genetic make-up regulate IL33 responsiveness of Th2 cells. ObjectiveWe investigated whether IL-1RL1 asthma risk haplotypes or asthma status influence IL-33-induced Th2 transcriptomic responses in vitro. MethodsCD4+ T cells from 16 asthma patients and matched controls, stratified for IL-1RL1 haplotype, were differentiated into Th2 effector cells, and re-stimulated in the presence or absence of IL-33, followed by RNA-sequencing and differential gene expression analysis. Association of IL-33-induced gene signatures with clinical parameters was tested in U-BIOPRED sputum transcriptomic data. ResultsPresence of IL-33 during Th2 cell re-stimulation results in extensive changes in gene expression, affecting a large proportion of the activated Th2 cell transcriptome. IL-33 induced more genes in Th2 cells from donors with asthma than in controls. However, the IL-33 effects were strongest in Th2 cells carrying the IL-1RL1 risk haplotype, as evidenced by a significantly increased effect size compared to controls. A gene signature of IL-33 induced genes in Th2 cells showed a strong positive correlation with macrophage counts and pauci-granulocytic asthma in sputum transcriptomic data from the U-BIOPRED study. ConclusionThe risk IL-1RL1 haplotype strongly increases the sensitivity of Th2 effector cell for IL-33-mediated regulation of gene expression, while asthma status has an independent effect. The IL-33 gene signature was not associated with type-2 high or eosinophilic asthma in sputum transcriptomic data from U-BIOPRED. Clinical OutcomeCellular sensitivity to IL-33 depends on genetic makeup and asthma disease status. Capsule summaryIL-33 strongly alters gene expression of activated Th2 cells, dependent on asthma disease status and IL-1RL1 risk haplotype. IL-33 driven gene signature in sputum transcriptomic data identifies pauci-granulocytic asthma.