Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells

J Exp Med. 2011 Aug 29;208(9):1875-87. doi: 10.1084/jem.20102516. Epub 2011 Aug 8.

Abstract

Human memory T cells (T(M) cells) that produce IL-17 or IL-22 are currently defined as Th17 or Th22 cells, respectively. These T cell lineages are almost exclusively CCR6(+) and are important mediators of chronic inflammation and autoimmunity. However, little is known about the mechanisms controlling IL-17/IL-22 expression in memory Th17/Th22 subsets. We show that common γ chain (γc)-using cytokines, namely IL-2, IL-7, and IL-15, potently induce Th17-signature cytokine expression (Il17a, Il17f, Il22, and Il26) in CCR6(+), but not CCR6(-), T(M) cells, even in CCR6(+) cells lacking IL-17 expression ex vivo. Inhibition of phosphoinositide 3-kinase (PI-3K) or Akt signaling selectively prevents Th17 cytokine induction by γc-cytokines, as does ectopic expression of the transcription factors FOXO1 or KLF2, which are repressed by PI-3K signaling. These results indicate that Th17 cytokines are tuned by PI-3K signaling in CCR6(+) T(M) cells, which may contribute to chronic or autoimmune inflammation. Furthermore, these findings suggest that ex vivo analysis of IL-17 expression may greatly underestimate the frequency and pathogenic potential of the human Th17 compartment.

Publication types

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

MeSH terms

  • Animals
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • Chronic Disease
  • Cytokines / genetics
  • Cytokines / immunology*
  • Humans
  • Immunologic Memory / physiology*
  • Inflammation / genetics
  • Inflammation / immunology
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / immunology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / immunology
  • Receptors, CCR6*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Th17 Cells / immunology*

Substances

  • CCR6 protein, human
  • CCR6 protein, mouse
  • Cytokines
  • Receptors, CCR6
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt