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bioRxiv · 10.1101/2022.12.05.519197

IL-6 prevents Th2 cell polarization by promoting SOCS3-dependent suppression of IL-2 signaling

Bachus, H.·McLaughlin, E.·Lewis, C.·Papillion, A. M.·Benveniste, E. N.·Hill, D. D.·Rosenberg, A. F.·Ballesteros-Tato, A.·Leon, B.
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Abstract

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.

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Bachus, H., McLaughlin, E., Lewis, C., Papillion, A. M., Benveniste, E. N., Hill, D. D., Rosenberg, A. F., Ballesteros-Tato, A., Leon, B.. 2022-12-08. IL-6 prevents Th2 cell polarization by promoting SOCS3-dependent suppression of IL-2 signaling. https://doi.org/10.1101/2022.12.05.519197

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