Interleukin 17-producing CD4+ Effector T Cells Develop via a Lineage Distinct From the T Helper Type 1 and 2 Lineages

Nat Immunol. 2005 Nov;6(11):1123-32. doi: 10.1038/ni1254. Epub 2005 Oct 2.

Abstract

CD4(+) T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (T(H)1) or T(H)2 lineages and instead favor the idea of a distinct effector lineage we call 'T(H)-17'. The development of T(H)-17 cells from naive precursor cells was potently inhibited by interferon-gamma (IFN-gamma) and IL-4, whereas committed T(H)-17 cells were resistant to suppression by T(H)1 or T(H)2 cytokines. In the absence of IFN-gamma and IL-4, IL-23 induced naive precursor cells to differentiate into T(H)-17 cells independently of the transcription factors STAT1, T-bet, STAT4 and STAT6. These findings provide a basis for understanding how inhibition of IFN-gamma signaling enhances development of pathogenic T(H)-17 effector cells that can exacerbate autoimmunity.

Publication types

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

MeSH terms

  • Animals
  • CD4 Antigens / immunology
  • Cell Lineage
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Interferon Type I / pharmacology
  • Interferon-gamma / pharmacology
  • Interleukin-17 / analysis
  • Interleukin-17 / biosynthesis*
  • Interleukin-23
  • Interleukin-23 Subunit p19
  • Interleukins / pharmacology
  • Mice
  • Mice, Mutant Strains
  • STAT1 Transcription Factor
  • STAT4 Transcription Factor
  • STAT6 Transcription Factor
  • T-Box Domain Proteins
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Th1 Cells / drug effects
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th2 Cells / drug effects
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • CD4 Antigens
  • DNA-Binding Proteins
  • Il23a protein, mouse
  • Interferon Type I
  • Interleukin-17
  • Interleukin-23
  • Interleukin-23 Subunit p19
  • Interleukins
  • STAT1 Transcription Factor
  • STAT4 Transcription Factor
  • STAT6 Transcription Factor
  • Stat1 protein, mouse
  • Stat4 protein, mouse
  • Stat6 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Trans-Activators
  • Transcription Factors
  • Interferon-gamma