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

Saikumar Jayalatha, A. K.; Ketelaar, M.; Hesse, L.; Badi, Y.; Kermani, N. Z.; Brouwer, S.; Dijk, N.; van den Berge, M.; Guryev, V.; Sayer, I.; Vonk, J.; Adcock, I.; Koppelman, G.; Nawijn, M.

doi:10.1101/2022.10.20.513024

bioRxiv · 10.1101/2022.10.20.513024

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

Saikumar Jayalatha, A. K.·Ketelaar, M.·Hesse, L.·Badi, Y.·Kermani, N. Z.·Brouwer, S.·Dijk, N.·van den Berge, M.·Guryev, V.·Sayer, I.·Vonk, J.·Adcock, I.·Koppelman, G.·Nawijn, M.

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Abstract

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.

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Saikumar Jayalatha, A. K., Ketelaar, M., Hesse, L., Badi, Y., Kermani, N. Z., Brouwer, S., Dijk, N., van den Berge, M., Guryev, V., Sayer, I., Vonk, J., Adcock, I., Koppelman, G., Nawijn, M.. 2022-10-21. IL-33 induced gene expression in activated Th2 effector cells is dependent on IL-1RL1 haplotype and disease status. https://doi.org/10.1101/2022.10.20.513024

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