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T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells
Open accessAbstract
Differentiation of naive CD4 + T cells into IFN-γ-producing T helper 1 (T H 1) cells is pivotal for protective immune responses against intracellular pathogens. T-bet, a recently discovered member of the T-box transcription factor family, has been reported to play a critical role in this process, promoting IFN-γ production. Although terminal T H 1 differentiation occurs over days, we now show that challenge of mice with a prototypical T H 1-inducing stimulus, Toxoplasma gondii soluble extract, rapidly induced IFN-γ and T-bet; T-bet induction was substantially lower in IFN-γ-deficient mice. Naive T cells expressed little T-bet, but this transcription factor was induced markedly by the combination of IFN-γ and cognate antigen. Human myeloid antigen-presenting cells showed T-bet induction after IFN-γ stimulation alone, and this induction was antagonized by IL-4 and granulocyte/macrophage colony-stimulating factor. Although T-bet was induced rapidly and directly by IFN-γ, it was not induced by IFN-α, lipopolysaccharide, or IL-1, indicating that this action of IFN-γ was specific. Moreover, T-bet induction was dependent on Stat1 but not Stat4. These data argue for a model in which IFN-γ gene regulation involves an autocrine loop, whereby the cytokine regulates a transcription factor that promotes its own production. These findings substantially alter the current view of T-bet in IFN-γ regulation and promotion of cell-mediated immune responses.
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“Priming of Th1 cells by IL-12 [188] and IFN-γ [189] results in expression of their master transcription factor T-bet [190]”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [189]
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T-bet is required for optimal proinflammatory CD4+ T-cell trafficking
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A method for the generation of standardized qualitative dynamical systems of regulatory networks
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T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17
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“One other important target of STAT1 is Tbx21, which encodes T-bet, the master regulator of Th1 cells (Lighvani et al., 2001).”
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“T-bet can also stimulate indirectly its own gene expression by inducing IFN- , which in turn activates T-bet gene expression (41, 42).”
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The host immune response to gastrointestinal nematode infection in sheep
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“However, this simple one STAT-one subset paradigm became more complicated when it was shown that STAT1 also contributed to Th1 differentiation (Afkarian et al., 2002; Lighvani et al., 2001), and STAT5 could function with STAT6 in the development of Th2 cells (Cote-Sierra et al.”
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“The T-box transcription factor T-bet has been termed a ‘‘master regulator’’ of Th1 cell development (Szabo et al., 2000; Szabo et al., 2002), and expression is induced during Th1 cell differentiation by interferon g (IFNg)-stimulated Stat1 activation (Lighvani et al., 2001; Afkarian et al., 2002).”
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“T-bet expression is promoted by the IFN-gR-STAT1 pathway (Lighvani et al., 2001; Afkarian et al., 2002) and by itself (Mullen et al.”
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“(e) STAT family Activation of STAT1 by IFN-γ is important for the induction of T-bet during in vitro Th1 differentiation [1, 93].”
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“In particular, type I IFN–driven ISGs (Mx-1, STAT-1, ISG-15, and IFIT-1) were the most significantly reduced (Figure 5D) (37,38).”
BackgroundSelf-citationIL-27 Limits IL-2 Production during Th1 Differentiation
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“For example, IFN- directly induces T-bet expression, providing positive feedback during TH1 differentiation [6].”
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Self-citationGene Silencing Quantitatively Controls the Function of a Developmental trans-Activator
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A Role for IL-27 in Early Regulation of Th1 Differentiation
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“Because IL-27 synergizes with IL-12 in primary IFN- production (1, 3, 4, 6) and IFN- is well known to play a critical role in Th1 differentiation through induction of T-bet and subsequent IL12R 2 expression (25, 26), we next examined the requirement for IFN- in IL-27-induced Th1 differentiation using IFN- -deficient n…”
BackgroundFurther Checkpoints in Th1 Development
Robinson, D. S., & O’Garra, A. (2002) · Immunity · doi:10.1016/s1074-7613(02)00331-x · Cited by 204
Metadata
- Authors
- Lighvani, A. A., Frucht, D. M., Jankovic, D., Yamane, H., Aliberti, J., Hissong, B. D., Nguyen, B. V., Gadina, M., Sher, A., Paul, W. E., & O'Shea, J. J.
- Affiliations
- National Institutes of Health (US)
- Lymphocyte Cell Biology Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Immunobiology Section, Laboratory of Parasitic Diseases, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Cell Biology Laboratory, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
- Corresponding author
- Frucht, David M.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-12-18
- Volume
- 98
- Issue
- 26
- Pages
- 15137-15142
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC64996
- OpenAlex
- W2011754426
- Cited by
- 783
- References
- 23
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 17 · 2023: 30 · 2022: 25 · 2021: 25 · 2020: 23 · 2019: 18 · 2018: 26 · 2017: 20 · 2016: 23 · 2015: 24 · 2014: 43 · 2013: 34 · 2012: 40
- FWCI
- 13.58
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Keywords
- T-bet, interferon-gamma, Toxoplasma gondii, STAT1, autocrine loop, IL-4, GM-CSF, myeloid antigen-presenting cells, naive CD4+ T cells, T-box transcription factor, cell-mediated immunity
- MeSH terms
- T-bet Transcription Factor, Animals, Antibodies, Monoclonal, Base Sequence, Cell Differentiation, Cells, Cultured, Dendritic Cells, Female, Humans, Interferon-gamma, Macrophages, Mice, Inbred C57BL, Transcription Factors, CD4-Positive T-Lymphocytes, Up-Regulation, DNA Primers, T-Box Domain Proteins, Mice
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