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

• Published in: Blood Vol. 108; no. 5; pp. 1595 - 1601
• Main Authors: Mathur, Anubhav N., Chang, Hua-Chen, Zisoulis, Dimitrios G., Kapur, Reuben, Belladonna, Maria Laura, Kansas, Geoffrey S., Kaplan, Mark H.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.09.2006; The Americain Society of Hematology; 2006 by The American Society of Hematology
• Subjects: Animals; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Cytokines - analysis; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunobiology; Immunophenotyping; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin-17 - metabolism; Mice; Mice, Knockout; Modulation of the immune response (stimulation, suppression); 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; Immune response; Immunophenotype; Rodentia; Th1 lymphocyte; Helper cell; Immune regulation; Interleukin 17; Vertebrata; Mammalia; Mouse; Animal; T-Lymphocyte; Transcription factor T-bet
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-04-015016

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 Th1β. Th1 or Th1β 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 Th1β cells promotes IFN-γ secretion but decreases IL-17 production. Although antigen-receptor stimulation of Th1β cells stimulates IL-17 production, it also induces the IFN-γ-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-/- Th1β cultures maintain the IL-17-secreting phenotype after 2 weeks of culture. Addition of IFN-γ to Tbx21-/- Th1β cultures cannot recover the progression to the Th1 phenotype, suggesting T-bet, rather than IFN-γ, mediates Th1β to Th1 progression. The transient nature of the Th1β phenotype suggests that these cells are a component of type I immunity and that T-bet expression is a critical determinant of Th1 versus Th1β cell fate.