PT - JOURNAL ARTICLE AU - Bachus, Holly AU - McLaughlin, Erin AU - Lewis, Crystal AU - Papillion, Amber M. AU - Benveniste, Etty N. AU - Hill, Dave Durrell AU - Rosenberg, Alexander F. AU - Ballesteros-Tato, André AU - León, Beatriz TI - IL-6 prevents Th2 cell polarization by promoting SOCS3-dependent suppression of IL-2 signaling AID - 10.1101/2022.12.05.519197 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.12.05.519197 4099 - http://biorxiv.org/content/early/2022/12/08/2022.12.05.519197.short 4100 - http://biorxiv.org/content/early/2022/12/08/2022.12.05.519197.full AB - Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE. However, the underlying mechanism by which IL-6 prevents the development of Th2-driven diseases remains unknown. Using a model of house-dust-mite (HDM)-induced Th2 differentiation and allergic airway inflammation, we show that IL-6 signaling in allergen-specific T cells was required to prevent Th2 development and subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. Importantly, we found that IL-6 turned off IL-2 signaling during early T cell activation and thus inhibited Th2 priming. Mechanistically, we found that IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of Suppressor Of Cytokine Signaling 3 (SOCS3). This mechanism could be mimicked by pharmacological Janus Kinase-1 (JAK1) inhibition. Collectively, our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions.Competing Interest StatementThe authors have declared no competing interest.