title: T-bet is a critical determinant in the instability of the IL-17-secreting T-helper phenotype.
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.
authors: Department Microbiology and Immunology, Indiana University School of Medicine, 702 Barnhill Dr, RI 2600, Indianapolis, IN 46202, USA.
authors: Anubhav N
authors: AN
authors: Mathur
authors: Hua-Chen
authors: HC
authors: Chang
authors: Dimitrios G
authors: DG
authors: Zisoulis
authors: Reuben
authors: R
authors: Kapur
authors: Maria Laura
authors: ML
authors: Belladonna
authors: Geoffrey S
authors: GS
authors: Kansas
authors: Mark H
authors: MH
authors: Kaplan