Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling

Nature. 2010 Oct 21;467(7318):967-71. doi: 10.1038/nature09447.

Abstract

CD4(+) T-helper cells that selectively produce interleukin (IL)-17 (T(H)17), are critical for host defence and autoimmunity. Although crucial for T(H)17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been proposed to be the factors responsible for initiating specification. Here we show that T(H)17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated T(H)17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. T-bet(+)RORγt(+) T(H)17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred T(H)17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for T(H)17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications.

Publication types

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

MeSH terms

  • Animals
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Autoimmunity / immunology
  • Cell Differentiation / drug effects
  • Central Nervous System / pathology
  • Inflammation
  • Interleukin-10
  • Interleukin-17 / metabolism
  • Interleukin-1beta / immunology
  • Interleukin-23 / immunology
  • Interleukin-23 / pharmacology
  • Interleukin-6 / immunology
  • Interleukin-9
  • Interleukins / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Mucous Membrane / cytology
  • Mucous Membrane / immunology
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Receptors, Interleukin / metabolism
  • Signal Transduction*
  • Th17 Cells / drug effects
  • Th17 Cells / metabolism
  • Th17 Cells / pathology*
  • Transforming Growth Factor beta*

Substances

  • Interleukin-17
  • Interleukin-1beta
  • Interleukin-23
  • Interleukin-6
  • Interleukin-9
  • Interleukins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Interleukin
  • Transforming Growth Factor beta
  • interleukin-23 receptor, mouse
  • Interleukin-10
  • interleukin-22

Associated data

  • GEO/GSE23505
  • GEO/GSE23681