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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1595-1601.
Prepublished online as a Blood First Edition Paper on May 2, 2006; DOI 10.1182/blood-2006-04-015016.
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IMMUNOBIOLOGY
T-bet is a critical determinant in the instability of the IL-17-secreting T-helper phenotype
Anubhav N. Mathur,
Hua-Chen Chang,
Dimitrios G. Zisoulis,
Reuben Kapur,
Maria Laura Belladonna,
Geoffrey S. Kansas, and
Mark H. Kaplan
From the Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis; the Walther Oncology Center, Indiana University School of Medicine, Indianapolis; the Department of Biochemistry, Indiana University School of Medicine, Indianapolis; the Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis; the Walther Cancer Institute, Indianapolis; the Department of Microbiology-Immunology, Northwestern University Medical School, Chicago IL; and the Department of Experimental Medicine, University of Perugia, Italy.
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 Th1 . Th1 or Th1 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 Th1 cells promotes IFN- secretion but decreases IL-17 production. Although antigen-receptor stimulation of Th1 cells stimulates IL-17 production, it also induces the IFN--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-/- Th1 cultures maintain the IL-17-secreting phenotype after 2 weeks of culture. Addition of IFN- to Tbx21-/- Th1 cultures cannot recover the progression to the Th1 phenotype, suggesting T-bet, rather than IFN-, mediates Th1 to Th1 progression. The transient nature of the Th1 phenotype suggests that these cells are a component of type I immunity and that T-bet expression is a critical determinant of Th1 versus Th1 cell fate.
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