Cited by 783T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisCytokine Signaling Pathways and Interactions

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T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells

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Lighvani, Andre A., Frucht, David M., Jankovic, Dragana, Yamane, Hidehiro, Aliberti, Julio, Hissong, Bruce D., Nguyen, Bai V., Gadina, Massimo, Sher, Alan, Paul, William E., O'Shea, John J.·2001·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.261570598PMC PMC64996

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Abstract

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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Enrichment of type 1 innate lymphoid cells in the course of human atherosclerotic plaque development suggests contribution to atherogenesis
Pertiwi, K. R., Teunissen, M. B. M., Krebbers, G., Willems, M. C. M., Huisman, L. C., Poelen, C., van der Wal, A. C., & de Boer, O. J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1354617 · Cited by 8
The potential of interleukin 12 receptor beta 2 (IL12RB2) and tumor necrosis factor receptor superfamily member 8 (TNFRSF8) gene as diagnostic biomarkers of oral lichen planus (OLP)
Jeon, S.-H., Jeon, E.-H., Lee, J., Kim, Y.-S., Yoon, H., Hong, S., & Lee, J.-H. (2015) · Acta Odontologica Scandinavica · doi:10.3109/00016357.2014.967719 · Cited by 8
Low Doses of Exogenous Interferon-γ Attenuated Airway Inflammation Through Enhancing Fas/FasL-Induced CD4 + T Cell Apoptosis in a Mouse Asthma Model
Yao, Y., Lu, S., Li, H., Lu, G., & Zhou, J. (2012) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2012.0016 · Cited by 8
The Role of T-Helper Cells in Atherosclerosis
Lu, X., Lu, D., Narayan, U., & Kakkar, V. V. (2011) · Cardiovascular & Hematological Agents in Medicinal Chemistry · doi:10.2174/187152511794182819 · Cited by 8
Genetic analysis of differentiation of T-helper lymphocytes
Wang, Q., Li, M., Xia, L. C., Gu, W., Zu, H., & Gao, M. (2013) · Genetics and Molecular Research · doi:10.4238/2013.april.2.13 · Cited by 8
“Human T helper cells are further categorized into two subpopulations: Th1 cells and Th2 cells [1].”
Background
Ubiquitin-hepatitis B core antigen-cytoplasmic transduction peptide enhances HBV-specific humoral and CTL immune responses in vivo
Song, L., Zhuo, M., Tang, Y., Chen, X., Tang, Z., & Zang, G. (2014) · International Immunopharmacology · doi:10.1016/j.intimp.2014.08.006 · Cited by 8
Antisense oligonucleotides-induced local blockade of T-bet expression leads to airway inflammation in rats1
Wang, G., Liu, C., Wang, Z., Jiang, L., Yan, C., & Feng-min, L. U. O. (2006) · Acta Pharmacologica Sinica · doi:10.1111/j.1745-7254.2006.00323.x · Cited by 8
T-bet-independent effects of IL-12 family cytokines on regulation of Th17 responses to experimental T. cruzi infection
Cobb, D. A., Hambright, D., & Smeltz, R. B. (2010) · Journal of Leukocyte Biology · doi:10.1189/jlb.0410238 · Cited by 8
“activators of T-bet [23, 24] and were logical candidates for testing.”
Background
The monocyte transcriptome during pregnancy in multiple sclerosis: prominent expression of the Fc-receptor CD64
Neuteboom, R. F., Verbraak, E., Wierenga‐Wolf, A. F., Voerman, J. S. A., van Meurs, M., Swagemakers, S. M. A., van der Spek, P. J., Steegers, E. A. P., de Groot, C. J. M., Laman, J. D., et al. (2010) · Multiple Sclerosis Journal · doi:10.1177/1352458510389628 · Cited by 8
T-bet expression in the iris and spleen parallels disease expression during endotoxin-induced uveitis
Li, B., Yang, P., Chu, L., Zhou, H., Huang, X., Zhu, L., & Kijlstra, A. (2006) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-006-0385-4 · Cited by 8
“Previous in vitro studies have shown that T-bet can be induced by IFN-γ but not by LPS [10].”
Result
Inhibition of G-Protein βγ Signaling Decreases Levels of Messenger RNAs Encoding Proinflammatory Cytokines in T Cell Receptor-Stimulated CD4+ T Helper Cells
Hynes, T. R., Yost, E. A., Hartle, C. M., Ott, B. J., & Berlot, C. H. (2015) · Journal of Molecular Signaling · doi:10.5334/1750-2187-10-1 · Cited by 8
“Previous reports described the roles of IFN-γ in TH1 differentiation [44], IL-2 in TH2 differentiation [31, 102] and TH17 differentiation [12, 13], IL-4 in TH2 differentiation [88, 89], and STAT4 in the differentiation of TH1 [100], TH2 [97], and TH17 T helper cell subtypes [69, 70].”
Background
Regulation of Asymmetric Division by Atypical Protein Kinase C Influences Early Specification of CD8+ T Lymphocyte Fates
Metz, P. J., Lopez, J. M., Kim, S. H., Akimoto, K., Ohno, S., & Chang, J. T. (2016) · Scientific Reports · doi:10.1038/srep19182 · Cited by 8
Th17 Cells: Orchestrators of Mucosal Inflammation and Potential Therapeutic Targets
Iraji, D., Oftedal, B. E., & Wolff, A. S. B. (2023) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.2023050360 · Cited by 7
Hyperlipidaemia elicits an atypical, T helper 1–like CD4+ T-cell response: a key role for very low-density lipoprotein
van Os, B. W., Vos, W. G., Bosmans, L. A., van Tiel, C. M., de Vries, C. J. M., den Toom, M., Beckers, L., Levels, J. H. M., van Wouw, S. A. E., Zelcer, N., et al. (2023) · European Heart Journal Open · doi:10.1093/ehjopen/oead013 · Cited by 7
Immunomodulation of potassium diformate in juvenile grass carp (Ctenopharyngodon idella) after Aeromonas hydrophila infection: T-cell differentiation and cytokine production
Chai, Q.-P., Wu, P., Jiang, W., Liu, Y., Ren, H., Jin, X., Feng, L., & Zhou, X. (2023) · Aquaculture · doi:10.1016/j.aquaculture.2023.740314 · Cited by 7
IFNγ at the early stage induced after cryo-thermal therapy maintains CD4+ Th1-prone differentiation, leading to long-term antitumor immunity
Wang, J., Lou, Y., Wang, S., Zhang, Z., You, J., Zhu, Y., Yao, Y., Hao, Y., Liu, P., & Xu, L. X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1345046 · Cited by 7
Drug Development from Natural Products Based on the Pathogenic Mechanism of Asthma
Kim, M.-H., Bae, C., Bok, S., Choi, H.-S., Ahn, T., Cho, S., & Park, D.-H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512469 · Cited by 8
“IFN-γ has incompatible functions; it acts as a stimulator and activates Th1 cell transcription factor (T-bet), and as a suppressor, it activates Th2 cell transcription factor (GATA-3), preventing eosinophilia and inhibiting asthmatic changes such as airway hyperreactivity, inflammation, and mucous hypersecretion in th…”
Background
Aflatoxin B1 Exposure Aggravates Neurobehavioral Deficits and Immune Dysfunctions of Th1, Th9, Th17, Th22, and T Regulatory Cell-Related Transcription Factor Signaling in the BTBR T+Itpr3tf/J Mouse Model of Autism
Alwetaid, M. Y., Almanaa, T. N., Bakheet, S. A., Ansari, M. A., Nadeem, A., Attia, S. M., Hussein, M. H., & Ahmad, S. F. (2023) · Brain Sciences · doi:10.3390/brainsci13111519 · Cited by 7
“T-bet is primarily triggered by the activation of STAT1 [69], which is associated with the production of IFN-γ [70].”
Fusion protein of tapasin and hepatitis B core antigen 18-27 enhances T helper cell type 1/2 cytokine ratio and antiviral immunity by inhibiting suppressors of cytokine signaling family members 1/3 in hepatitis B virus transgenic mice
Tang, Y., Chen, X., Zhang, Y., Tang, Z., Zhuo, M., Li, D., WANG, P., Zang, G., & Yu, Y. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.1947 · Cited by 7
Transcription Factor T-bet Attenuates the Development of Elastase-induced Emphysema in Mice
Hayashi, S., Matsuno, Y., Tsunoda, Y., Sakurai, H., Kiwamoto, T., Morishima, Y., Ishii, Y., Yoh, K., Takahashi, S., & Hizawa, N. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2018-0109oc · Cited by 7
Sclerostin domain-containing protein 1 is dispensable for the differentiation of follicular helper and follicular regulatory T cells during acute viral infection.
Hu, J., Wu, J. S., Li, Y., Wang, Z., Tang, J., Li, Z., Li, H., Huang, Q., Ye, L., & Xu, L. (2019) · PubMed Central · Cited by 7
Transcription factor expression in B-cell precursor-leukemia cell lines: preferential expression of T-bet
Harashima, A., Matsuo, Y., Drexler, H. G., Okochi, A., Motoda, R., Tanimoto, M., & Orita, K. (2005) · Leukemia Research · doi:10.1016/j.leukres.2004.12.010 · Cited by 7
Pseudokinase STK40 promotes T H 1 and T H 17 cell differentiation by targeting FOXO transcription factors
Tao, Y., Jiang, Z., Wang, H., Li, J., Li, X., Ni, J., Liu, J., Xiang, H., Guan, C., Cao, W., et al. (2024) · Science Advances · doi:10.1126/sciadv.adp2919 · Cited by 8
“IFN-γ is not only an effector cytokine produced by T H 1 but also a key cytokine that initiates downstream signaling cascade responses to form T H 1 cells ( 55 ).”
T-cell-derived IFN-γ suppresses T follicular helper cell differentiation and antibody responses
Sala, E., Nelli, M., Laura, C., Lucia, P. D., Beccaría, C. G., Bono, E. B., Mangione, M., Marotta, D., Sperto, V., Grillo, M., et al. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00414-3 · Cited by 6
“Importantly, we found that the IFN-γ responsible for T FH suppression is T cell-derived but does not act on CD4 + T cells themselves, unlike to what previously reported for T cell expansion and T H 1 maintenance (Bradley et al, 1996; Lighvani et al, 2001; Whitmire et al, 2005).”
Influential
T Cells with Commitment Issues
Schneider, R. (2010) · Science Signaling · doi:10.1126/scisignal.3118jc3 · Cited by 6
High‐fat‐diet induced obesity and diabetes mellitus in Th1 and Th2 biased mice strains: A brief overview and hypothesis
Sankaran, P. S. (2023) · Chronic Diseases and Translational Medicine · doi:10.1002/cdt3.57 · Cited by 6
T cell intrinsic STAT1 signaling prevents aberrant Th1 responses during acute toxoplasmosis
Schultz, A. B., Kugler, D. G., Nivelo, L. A., Vitari, N., Doyle, L. P., Ristin, S., Hennighausen, L. G., O’Shea, J. J., Jankovic, D. L., & Villarino, A. V. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1212190 · Cited by 6
“Chief among these is its ability to induce expression of T-bet ( Tbx21 ), a transcription factor that underlies key aspects of the Th1 differentiation program (20 – 23).”
Self-citation
Effect of dietary supplementation of fish oil for lactating sows and weaned piglets on piglet Th polarization
Luo, J., Huang, F. R., Xiao, C., Chen, W., Jiang, S., & Peng, J. (2009) · Livestock Science · doi:10.1016/j.livsci.2009.08.002 · Cited by 6
“This cytokine also can induce a potential positive feedback loop to promote the expression of IL-12Rβ2 and IFN-γ (Lighvani et al., 2001; Szabo et al., 2003).”
Background
Tat-mediated Intracellular Delivery of T-bet Protein into THP-1 Cells can Induce Th1-Type Response
Yang, M., Wang, S., Wang, S., Ma, J., Xu, X., Mao, C., Ma, B., Tong, J., Qiu, G., Shao, Q., et al. (2008) · Immunological Investigations · doi:10.1080/08820130701690725 · Cited by 6
Cytokines in the Treatment of Cancer
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Interferon-γ and T-bet expression in a patient with toxoplasmic lymphadenopathy
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Regulation of T cells in asthma: implications for genetic manipulation
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Transcription Factors That Regulate Helper T Cell Differentiation
Usui, T. (2007) · Japanese Journal of Clinical Immunology · doi:10.2177/jsci.30.419 · Cited by 6
The growing complexity of TGF‐β as a T‐cell regulator
Kemeny, D. M., & MacAry, P. A. (2005) · Immunology · doi:10.1111/j.1365-2567.2005.02164.x · Cited by 6
Expression level of costimulatory receptor ICOS is critical for determining the polarization of helper T cell function
Watanabe, S., Ogawa, S., Hara, Y., Tanabe, K., Toma, H., & Abe, R. (2006) · Transplant Immunology · doi:10.1016/j.trim.2006.01.002 · Cited by 6
New asthma targets: recent clinical and preclinical advances
Greenfeder, S. A., & Anthes, J. C. (2002) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(02)00349-6 · Cited by 6
Cellular Factors Targeting APCs to Modulate Adaptive T Cell Immunity
Visperas, A., Do, J., & Min, B. (2014) · Journal of Immunology Research · doi:10.1155/2014/750374 · Cited by 6

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.
ORCID: Frucht, David M.
Jankovic, Dragana
Yamane, Hidehiro
Gadina, Massimo
Sher, Alan
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
DOI: 10.1073/pnas.261570598
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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T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells

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