T-bet is a critical determinant in the instability of the IL-17-secreting T-helper phenotype

Blood. 2006 Sep 1;108(5):1595-601. doi: 10.1182/blood-2006-04-015016. Epub 2006 May 2.

Abstract

IL-23, an IL-12-related cytokine, induces an IL-17-secreting T-helper phenotype that is involved in autoimmune diseases and host defense against certain pathogens. Although the transcription factors required for development of IL-23-stimulated cells are unknown, we show that T-bet is a critical negative regulator of the IL-23-primed T-cell phenotype, which we term Th1beta. Th1 or Th1beta Tbx21-/- cultures secrete higher than WT levels of IL-17 in response to T-cell receptor (TCR) or IL-23 + IL-18 stimulation. Ectopic T-bet expression in Th1beta cells promotes IFN-gamma secretion but decreases IL-17 production. Although antigen-receptor stimulation of Th1beta cells stimulates IL-17 production, it also induces the IFN-gamma-independent expression of T-bet and progression to a Th1 cytokine secretion pattern. T-bet is required for the progression to the Th1 phenotype, because Tbx21-/- Th1beta cultures maintain the IL-17-secreting phenotype after 2 weeks of culture. Addition of IFN-gamma to Tbx21-/- Th1beta cultures cannot recover the progression to the Th1 phenotype, suggesting T-bet, rather than IFN-gamma, mediates Th1beta to Th1 progression. The transient nature of the Th1beta phenotype suggests that these cells are a component of type I immunity and that T-bet expression is a critical determinant of Th1 versus Th1beta cell fate.

Publication types

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

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cytokines / analysis
  • Immunophenotyping
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism*
  • Mice
  • Mice, Knockout
  • Polymerase Chain Reaction
  • Receptors, Antigen, T-Cell / immunology
  • Spleen / cytology
  • Spleen / immunology
  • T-Box Domain Proteins
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Th1 Cells / immunology
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / immunology*

Substances

  • Cytokines
  • Interleukin-17
  • Receptors, Antigen, T-Cell
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transcription Factors
  • Interferon-gamma