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

Cell Mol Immunol. 2023 Jun;20(6):651-665. doi: 10.1038/s41423-023-01012-1. Epub 2023 Apr 12.


Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE levels. 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 cell differentiation and allergic airway inflammation, we showed that IL-6 signaling in allergen-specific T cells was required to prevent Th2 cell differentiation and the subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. We found that IL-6 turned off IL-2 signaling during early T-cell activation and thus inhibited Th2 priming. Mechanistically, 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.

Keywords: IL-2; IL-6; JAK1 inhibitor; SOCS3; Th2 cell polarization.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cytokines / metabolism
  • Humans
  • Immunoglobulin E
  • Inflammation
  • Interleukin-2
  • Interleukin-6*
  • Suppressor of Cytokine Signaling 3 Protein
  • Th2 Cells* / metabolism


  • Interleukin-6
  • Interleukin-2
  • Immunoglobulin E
  • Cytokines
  • SOCS3 protein, human
  • Suppressor of Cytokine Signaling 3 Protein