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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 expressed by T cells, NK cells, B cells, monocytes/macrophages, and dendritic cells (15, 24 ).”
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“Important transcription factors for TH1 cells are T-bet and STAT4 [5,13,14], and important transcription factors for TH2 cells are GATA-3 and STAT6 [5,15–19].”
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“Indeed, while Stat4 deficient mice have defects in Th1 differentiation, treatment with IFNγ resulted in increased Tbet expression (Lighvani et al. 2001) and treatment of wild type cells with either IL-12 or IFNγ-induced Tbet expression (Zhu et al. 2012), indicating Th1 differentiation can occur in…”
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“Since T-bet reportedly functions downstream of STAT1 [10, 11, 13, 76] and the IFN-γ R is dispensable for T-betdependent IFN-γ expression, it was then explored whether the STAT1-activating IL-27R signaling regulates T-betdependent IFN-γ expression by CD8+ T cells in vivo [74].”
BackgroundInfluentialCellular and population plasticity of helper CD4+ T cell responses
Magombedze, G., Reddy, P. B. J., Eda, S., & Ganusov, V. V. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00206 · Cited by 72
“Th1 effectors express a transcription factor T-bet and secrete the cytokines IFN-γ and TNF-α; these cells play an essential role in inhibiting replication of intracellular pathogens such as viruses (Hsieh et al., 1993; Lighvani et al., 2001; Kenneth et al., 2008).”
BackgroundImpaired Accumulation and Function of Memory CD4 T Cells in Human IL-12 Receptor β1 Deficiency
Cohen, A. C., Tu, W., Enright, A. M., Giffon, T. D., Malefyt, R. D. W., Gutierrez, K. M., & Lewis, D. B. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.1.597 · Cited by 66
“In support of this theory, recent data show that IFN- induces both T-bet and IFN- production in a positive feedback loop and may act early in T cell differentiation to increase IL-12R 2 (48).”
ResultInterferon γ Enhances Both In Vitro and In Vivo Priming of CD4+ T Cells for IL-4 Production
Boček, P., Foucras, G., & Paul, W. E. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20032014 · Cited by 67
Self-citationHelper T cell differentiation enters a new era: Le Roi est mort; vive le Roi!
Tato, C. M., Laurence, A. D. J., & O’Shea, J. J. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20060522 · Cited by 66
Self-citationLi, H., Wang, H., Sokulsky, L. A., Liu, S., Yang, R. R., Liu, X., Zhou, L., Li, J., Huang, C., Li, F., et al. (2020) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.09.032 · Cited by 63
Expression Regulation and Function of T-Bet in NK Cells
Huang, C. Y., & Bi, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.761920 · Cited by 61
Mattsson, J., Schön, K., Ekman, L., Fahlén‐Yrlid, L., Yrlid, U., & Lycke, N. Y. (2014) · Mucosal Immunology · doi:10.1038/mi.2014.111 · Cited by 63
Das, U. N. (2010) · Journal of Inflammation Research · doi:10.2147/jir.s9425 · Cited by 63
Tomio, A., Schust, D. J., Kawana, K., Yasugi, T., Kawana, Y., Mahalingaiah, S., Fujii, T., & Taketani, Y. (2008) · Immunology and Cell Biology · doi:10.1038/icb.2008.29 · Cited by 63
Dominant Th2 Differentiation of Human Regulatory T Cells upon Loss of FOXP3 Expression
Hansmann, L., Schmidl, C., Kett, J., Steger, L., Andreesen, R., Hoffmann, P., Rehli, M., & Edinger, M. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1102288 · Cited by 64
Xiao, X., Kroemer, A., Gao, W., Ishii, N., Demirci, G., & Li, X. C. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.5.3193 · Cited by 63
“Similarly as in previous reports (30), T-bet gene transcripts were highly expressed in CD4 T effector cells stimulated in the presence of IFN- (Fig.”
BackgroundResultA Key Pathogenic Role for the Stat1/T–Bet Signaling Pathway in T–Cell-Mediated Liver Inflammation
Siebler, J., Wirtz, S. J., Klein, S., Protschka, M., Blessing, M., Galle, P. R., & Neurath, M. F. (2003) · Hepatology · doi:10.1016/j.hep.2003.09.020 · Cited by 62
Jackson, J. A., Begon, M. E., Birtles, R. J., Paterson, S., Friberg, I. M., Hall, A. J., Lowe, A., Ralli, C., Turner, A., ZAWADZKA, M., et al. (2010) · Molecular Ecology · doi:10.1111/j.1365-294x.2010.04907.x · Cited by 61
“Thus, expression of Tbet and IFN-c was very highly associated in mitogen-stimulated splenocytes, as might be predicted from the positive feedback loop between them in CD4+ T-cells (Lighvani et al. 2001; Mullen et al. 2001).”
BackgroundDevelopment and regulation of cell-mediated immunity in experimental Leishmaniasis
Scott, P. (2003) · Immunologic Research · doi:10.1385/ir:27:2-3:489 · Cited by 61
Overview of Orchestration of CD4+ T Cell Subsets in Immune Responses
Sun, B., & Zhang, Y. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-94-017-9487-9_1 · Cited by 67
The role of IL‐27 in the development of T‐cell responses during parasitic infections
Hunter, C. A., Villarino, A. V., Artis, D., & Scott, P. (2004) · Immunological Reviews · doi:10.1111/j.0105-2896.2004.00213.x · Cited by 60
Allie, S. R., & Randall, T. D. (2017) · Clinical Science · doi:10.1042/cs20160259 · Cited by 63
The adjuvant activity of CpG DNA requires T-bet expression in dendritic cells
Lugo‐Villarino, G., Ito, S.-I., Klinman, D. M., & Glimcher, L. H. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506638102 · Cited by 60
Behera, A. K., Kumar, M., Lockey, R. F., & Mohapatra, S. S. (2002) · Human Gene Therapy · doi:10.1089/104303402760293547 · Cited by 60
Immunometabolism in biofilm infection: lessons from cancer
Mirzaei, R., Sabokroo, N., Ahmadyousefi, Y., Motamedi, H., & Karampoor, S. (2022) · Molecular Medicine · doi:10.1186/s10020-022-00435-2 · Cited by 60
IL-36γ/IL-1F9, an Innate T-bet Target in Myeloid Cells
Bachmann, M., Scheiermann, P., Härdle, L., Pfeilschifter, J. M., & Mühl, H. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.385443 · Cited by 59
“We furthermore confirm by real-time PCR previous observations (6) on robust T-bet mRNA induction in monocyte-derived DC under the influence of IFN , which was used as a single stimulus or in combination with IL-1 plus TNF .”
BackgroundResultInfluentialUnique Features of Naive CD8+ T Cell Activation by IL-2
Cho, J.-H., Kim, H.-O., Kim, K., Yang, D., Surh, C. D., & Sprent, J. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1302293 · Cited by 59
Fong, F. L. Y., Kirjavainen, P. V., & El-Nezami, H. (2016) · Scientific Reports · doi:10.1038/srep22845 · Cited by 56
IRF1 supports DNA binding of STAT1 by promoting its phosphorylation
Zenke, K., Muroi, M., & Tanamoto, K. (2018) · Immunology and Cell Biology · doi:10.1111/imcb.12185 · Cited by 56
“Similar but distinct positive feedback systems in JAK– STAT signaling were also reported in CD4-positive T cells, in which IFN-c can be induced by the T-cellspecific transcription factor T-bet, a downstream target gene of STAT1.”
BackgroundInfluentialKhademi, F., Derakhshan, M., Avarvand, A. Y., Tafaghodi, M., & Soleimanpour, S. (2017) · Expert Review of Vaccines · doi:10.1080/14760584.2018.1406309 · Cited by 55
Ai, K., Li, K., Jiao, X., Zhang, Y., Li, J., Zhang, Q., Wei, X., & Yang, J. (2022) · PLoS Pathogens · doi:10.1371/journal.ppat.1010913 · Cited by 55
O’Malley, J. T., Sehra, S., Thieu, V. T., Yu, Q., Chang, H., Stritesky, G. L., Nguyen, E., Mathur, A. N., Levy, D. E., & Kaplan, M. H. (2008) · Immunology · doi:10.1111/j.1365-2567.2008.03037.x · Cited by 56
Cauwelaert, N. D., Desbien, A. L., Hudson, T. E., Pine, S. O., Reed, S. G., Coler, R. N., & Orr, M. T. (2016) · PLoS ONE · doi:10.1371/journal.pone.0146372 · Cited by 57
Opposing Roles of STAT4 and Dnmt3a in Th1 Gene Regulation
Pham, D., Yu, Q., Walline, C. C., Muthukrishnan, R., Blum, J. S., & Kaplan, M. H. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1203229 · Cited by 55
Rosas, L. E., Keiser, T. L., Pyles, R., Durbin, J. E., & Satoskar, A. R. (2003) · European Journal of Immunology · doi:10.1002/eji.200323163 · Cited by 54
Modulation of the tumor micro-environment by CD8+ T cell-derived cytokines
Hoekstra, M. E., Vijver, S. V., & Schumacher, T. N. (2021) · Current Opinion in Immunology · doi:10.1016/j.coi.2021.03.016 · Cited by 56
Cell Biology of T Cell Activation and Differentiation
Santana, M. A., & Esquivel-Guadarrama, F. R. (2006) · International review of cytology · doi:10.1016/s0074-7696(06)50006-3 · Cited by 61
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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