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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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“First, the expression of T-bet in naive T cells induced by IL-27, IFNg, or other yet unidentified inducers (Lighvani et al., 2001; Kamiya et al., 2004); second, differentiation of IFNg producing Th1 cells from T-bet expressing T cells induced by IL-12 (Mullen et al., 2001; Szabo et al., 2002); and…”
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“T-bet was previously shown to be induced by IFN- +γin a STAT-1 dependent fashion [ 36 ].”
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“Naive CD4 T cells produce low levels of IFN-g within 24 h of stimulation with Ag, and this early IFN-g acts in an autocrine manner to induce Stat1-dependent upregulation of T-bet that is important for driving Th1 differentiation (13, 14).”
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“It has been reported that T-bet is regulated by IFN-c signaling through STAT1 activation in the context of TCR ligation ( 10 ,11) and induces chromatin remodeling of the ifn-c locus (48).”
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“…was performed as described previously (Witt et al., 2002). interferon-, interferon-, IL-2, and IL-12, which have been used for induction of T-bet in recent literature and observed the most striking effect on T-bet induction when stimulating with IL-2 (Lighvani et al., 2001; Ylikoski et al., 2005).”
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Multiple Functions of B Cells in the Pathogenesis of Systemic Lupus Erythematosus
Ma, K., Du, W., Wang, X., Yuan, S., Cai, X., Liu, D. J., Li, J., & Lu, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20236021 · Cited by 121
The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival
Felices, M., & Berg, L. J. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.5.3007 · Cited by 113
“This notion is at odds with current evidence regarding the regulation of T-bet transcription, which in conventional CD4 T cells has been shown to be dependent solely on IFN- receptor signaling, and independent of TCR signaling (57).”
ResultZygmunt, B. M., & Veldhoen, M. (2011) · Advances in immunology · doi:10.1016/b978-0-12-387664-5.00005-4 · Cited by 116
“In this way, IFNg promotes TH1 development, IL-4 supports TH2 cells, and TGFb initiates the iTREG differentiation program, while IL-21 may succor the TH17 lineage (Chen et al., 2003; Korn et al., 2007; Le Gros et al., 1990; Lighvani et al., 2001; Noben-Trauth et al., 2002; Swain et al., 1990).”
BackgroundTIM Family of Genes in Immunity and Tolerance
Kuchroo, V. K., Meyers, J. H., Umetsu, D. T., & DeKruyff, R. H. (2006) · Advances in immunology · doi:10.1016/s0065-2776(06)91006-2 · Cited by 111
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“T-bet expression and IL-12R2 gene transcription in response to T-bet have previously been shown to depend upon IFN-/IFN-R or IL-27/WSX-1 signaling through STAT1 during in vitro stimulation ( 24 , 30, 50).”
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Gfi-1 plays an important role in IL-2-mediated Th2 cell expansion
Zhu, J., Jankovic, D. L., Grinberg, A., Guo, L., & Paul, W. E. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608981103 · Cited by 113
Self-citationTh1 memory: implications for vaccine development
Foulds, K. E., Wu, C. Y., & Seder, R. A. (2006) · Immunological Reviews · doi:10.1111/j.0105-2896.2006.00400.x · Cited by 110
Predominance of type 1 CD4+T cells in human abdominal aortic aneurysm
Galle, C., Schandené, L., Stordeur, P., Peignois, Y., Ferreira, J., Wautrecht, J.-C., Dereume, J.-P., & Goldman, M. (2005) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2005.02938.x · Cited by 108
In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment
Duralı, D., de Herve, M.-G. D. G., Giron‐Michel, J., Azzarone, B. G., Delfraissy, J., & Taoufik, Y. (2003) · Blood · doi:10.1182/blood-2003-02-0518 · Cited by 111
Sirén, J., Sareneva, T., Pirhonen, J., Strengell, M., Veckman, V., Julkunen, I., & Matikainen, S. (2004) · Journal of General Virology · doi:10.1099/vir.0.80105-0 · Cited by 107
“These results show that, in addition to IFN-c (Afkarian et al., 2002; Lighvani et al., 2001) and IL12 (Szabo et al., 2000), IFN-a also upregulates T-bet gene expression in NK cells and thus enhances innate immune responses.”
ResultFrom cells to signaling cascades: manipulation of innate immunity byToxoplasma gondii
Denkers, E. (2003) · FEMS Immunology & Medical Microbiology · doi:10.1016/s0928-8244(03)00279-7 · Cited by 105
Regulation of THI differentiation – controlling the controllers
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Self-citationCytokines and their role in lymphoid development, differentiation and homeostasis
Hofmann, S. R., Ettinger, R., Zhou, Y., Gadina, M., Lipsky, P. E., Siegel, R. M., Candotti, F., & O’Shea, J. J. (2002) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/00130832-200212000-00004 · Cited by 103
Self-citationRegulation of the T helper cell type 1 transcription factor T-bet in coeliac disease mucosa
Monteleone, I., Monteleone, G., Blanco, G. D. V., Vavassori, P., Cucchiara, S., MacDonald, T. T., & Pallone, F. (2004) · Gut · doi:10.1136/gut.2003.030551 · Cited by 103
Transcriptional mechanisms that regulate T helper 1 cell differentiation
Oestreich, K. J., & Weinmann, A. S. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.12.004 · Cited by 102
What determines Th2 differentiation, in vitro and in vivo?
Paul, W. E. (2010) · Immunology and Cell Biology · doi:10.1038/icb.2010.2 · Cited by 99
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“Th1 cell responses, induced by some bacterial or viral infections, are driven by interleukin-12 (IL-12) and the transcription factors Stat4 and T-bet (Lighvani et al., 2001; Szabo et al., 2000).”
Self-citationCellular and molecular mechanisms of CD8(+) T cell differentiation, dysfunction and exhaustion
Verdon, D. J., Mulazzani, M., & Jenkins, M. R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197357 · Cited by 98
Stolarczyk, É., Vong, C. T., Perucha, E., Jackson, I., Cawthorne, M. A., Wargent, E. T., Powell, N., Canavan, J. B., Lord, G. M., & Howard, J. K. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.02.019 · Cited by 98
“In addition to being a direct target of T-bet, IFN-g has an important role in inducing the expression of T-bet in a STAT1-dependent manner (Lighvani et al., 2001), indicating that some of the effects attributed to IFN-g may be due to its effect on T-bet expression.”
BackgroundTarasenko, T., Kole, H. K., Chi, A. W., Mentink‐Kane, M. M., Wynn, T. A., & Bolland, S. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0704853104 · Cited by 97
The TCR-mediated signaling pathways that control the direction of helper T cell differentiation
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“The binding of IFN- to its receptor activates the tyrosine phosphorylation of Jak1 and Stat1, and through nuclear translocation and transcriptional activity of Stat1 homodimers, this pathway stimulates the expression of genes encoding proteins important for Th1 development, such as the transcription factors T-bet and…”
BackgroundIssues in T‐helper 1 development – resolved and unresolved
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Mangiferin Attenuates Th1/Th2 Cytokine Imbalance in an Ovalbumin-Induced Asthmatic Mouse Model
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Monocytes control natural killer cell differentiation to effector phenotypes
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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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