A functional IL-13 receptor is expressed on polarized murine CD4+ Th17 cells and IL-13 signaling attenuates Th17 cytokine production

J Immunol. 2009 May 1;182(9):5317-21. doi: 10.4049/jimmunol.0803868.

Abstract

IL-17A is produced from Th17 cells, and is involved in many autoimmune and inflammatory diseases. IL-13R has not previously been reported to be functionally expressed on T cells; however, we found that purified BALB/c CD4(+) cells polarized to Th17 with TGF-beta, IL-6, and IL-23 have increased mRNA and protein expression of IL-13R alpha1 and mRNA expression of IL-4R alpha compared with Th0, Th1, or Th2 polarized cells. The addition of IL-13 at Th17 polarization negatively regulated IL-17A and IL-21 expression, and reduced the number of CD4(+) T cells producing IL-17A. Further, adding IL-13 at the time of Th17 cell restimulation attenuated IL-17A expression. CD4(+) Th17 polarized cells from IL-4 knockout (KO) mice also had IL-13-induced inhibition of IL-17A production, but this was not observed in IL-4R KO and STAT6 KO mice. Addition of IL-13 at polarization increased IL-13R expression in wild-type Th17 cells. Further, IL-13 administration during Th17 polarization down-regulated retinoic acid-related-gammaT, the transcription required for Th17 development; increased STAT6 phosphorylation, and up-regulated GATA3, the transcription factor activated during the development of Th2 cells. This IL-13-mediated effect was specific to Th17 cells as IL-13 neither decreased IFN-gamma expression by Th1 cells nor affected Th2 cell production of IL-4. Collectively, we have shown that Th17 cells express a functional IL-13R and that IL-13 negatively regulates IL-17A and IL-21 production by decreasing retinoic acid-related-gammaT expression and while increasing phosphorylation of STAT6 and GATA3 expression. Therefore, therapeutic intervention inhibiting IL-13 production could have adverse consequences by up-regulating Th17 inflammation in certain disease states.

Publication types

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

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / immunology
  • Cell Polarity / immunology
  • Cells, Cultured
  • Down-Regulation / immunology*
  • Female
  • Growth Inhibitors / physiology*
  • Interleukin-13 / physiology*
  • Interleukin-17 / antagonists & inhibitors*
  • Interleukin-17 / biosynthesis
  • Lymphocyte Count
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Receptors, Interleukin-13 / biosynthesis*
  • Receptors, Interleukin-13 / genetics
  • Receptors, Interleukin-13 / physiology
  • Signal Transduction / immunology*
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism

Substances

  • Growth Inhibitors
  • Interleukin-13
  • Interleukin-17
  • Receptors, Interleukin-13