IL-9 sensitizes human T_H2 cells to proinflammatory IL-18 signals in atopic dermatitis

Background: T_H2 cells crucially contribute to the pathogenesis of atopic dermatitis (AD) by secreting high levels of IL-13 and IL-22. Yet the upstream regulators that activate T_H2 cells in AD skin remain unclear. IL-18 is a putative upstream regulator of T_H2 cells because it is implicated in AD pathogenesis and has the capacity to activate T cells. Objective: We sought to decipher the role of IL-18 in T_H2 responses in blood and skin of AD patients. Methods: Peripheral blood mononuclear cells and skin biopsy samples from AD patients and healthy donors were used. Functional assays were performed ex vivo using stimulation or blocking experiments. Analysis was performed by flow cytometry, bead-based multiplex assays, RT-qPCR, RNA-Seq, Western blot, and spatial sequencing. Results: IL-18Rα⁺ T_H2 cells were enriched in blood and lesional skin of AD patients. Of all the cytokines for which T_H2 cells express the receptor, only IL-9 was able to induce IL-18R via an IL-9R–JAK1/JAK3-STAT1 signaling pathway. Functionally, stimulation of circulating T_H2 cells with IL-18 induced secretion of IL-13 and IL-22, an effect that was enhanced by costimulation with IL-9. Mechanistically, IL-18 induced T_H2 cytokines via activation of IRAK4, NF-κB, and AP-1 signaling in T_H2 cells, and neutralization of IL-18 inhibited these cytokines in cultured explants of AD skin lesions. Finally, IL-18 protein levels correlated positively with disease severity in lesional AD skin. Conclusion: Our data identify a novel IL-9/IL-18 axis that contributes to T_H2 responses in AD. Our findings suggest that both IL-9 and IL-18 could represent upstream targets for future treatment of AD.