Late Breaking Abstract - Enhanced IL-33 response in differentiated human TH2 cells carrying the IL-1RL1 asthma risk genotype

Rationale:IL-33 and its receptor IL-1RL1 are important asthma genes. T helper-2 (TH2) cells present in asthmatic airway wall contribute to chronic inflammation and epithelial remodeling. TH2 cells express IL-1RL1 and respond to IL-33 by increased cytokine production upon stimulation. We aimed to test the extent of the IL-33-driven modification of TH2 cell activation based on asthma-susceptibility alleles of IL-1RL1 gene. Methods: Results: Presence of IL-33 during CD3/CD28 stimulation of TH2 effector cells in-vitro results in extensive changes in gene expression, affecting up to 40% of the transcriptomic changes induced by TH2 cell activation. Nearly, 5-fold change in gene expression was induced by IL-33 in TH2 cells carrying the IL-1RL1 risk haplotype compared to the protective haplotype. In addition, significant differences in IL-33 regulated genes were observed between TH2 cells derived from healthy controls and asthma patients. Conclusions: The asthma-associated IL-1RL1 haplotype strongly increased the sensitivity of TH2 effector cell for IL-33-mediated regulation of gene expression, while disease status also has an independent effect. IL-33 in the airway wall will contribute to chronic inflammation maintained by TH2 effector cells mainly in patients with asthma carrying the IL-1RL1 asthma risk alleles.