Sensitivity and resistance to regulation by IL-4 during Th17 maturation

J Immunol. 2011 Nov 1;187(9):4440-50. doi: 10.4049/jimmunol.1002860. Epub 2011 Sep 26.


Th17 cells are highly pathogenic in a variety of immune-mediated diseases, and a thorough understanding of the mechanisms of cytokine-mediated suppression of Th17 cells has great therapeutic potential. In this article, we characterize the regulation of both in vitro- and in vivo-derived Th17 cells by IL-4. We demonstrate that IL-4 suppresses reactivation of committed Th17 cells, even in the presence of TGF-β, IL-6, and IL-23. Downregulation of IL-17 by IL-4 is dependent on STAT6 and mediated by inhibition of STAT3 binding at the Il17a promoter. Although Th1 cytokines were shown to induce IFN-γ expression by Th17 cells, IL-4 does not induce a Th2 phenotype in Th17 cells. Suppression by IL-4 is stable and long-lived when applied to immature Th17 cells, but cells that have undergone multiple rounds of stimulation, either in vivo during a Th17-mediated inflammatory disease, or in vitro, become resistant to suppression by IL-4 and lose the ability to signal through IL-4R. Thus, although IL-4 is a potent suppressor of the Th17 genetic program at early stages after differentiation, prolonged stimulation renders Th17 cells impervious to regulatory cytokines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • GATA3 Transcription Factor / physiology
  • Growth Inhibitors / antagonists & inhibitors
  • Growth Inhibitors / physiology*
  • Immunophenotyping
  • Interleukin-17 / antagonists & inhibitors*
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / deficiency
  • Interleukin-17 / genetics
  • Interleukin-4 / antagonists & inhibitors
  • Interleukin-4 / physiology*
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Transgenic
  • Protein Binding / genetics
  • Protein Binding / immunology
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / metabolism
  • STAT6 Transcription Factor / physiology
  • Th17 Cells / cytology*
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism
  • Th2 Cells / immunology
  • Th2 Cells / metabolism


  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Growth Inhibitors
  • Interleukin-17
  • STAT3 Transcription Factor
  • STAT6 Transcription Factor
  • Stat3 protein, mouse
  • Stat6 protein, mouse
  • Interleukin-4