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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Background
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Background
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BackgroundResult
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“In T cells, T-bet–dependent IFN- production does not appear to be counterbalanced by GATA-3, unlike in T cells (50, 51).”
Background
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“Stat1 activation, induces T-bet expression (18, 22, 23), whereas”
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“Although it was suggested that T-bet expression may be stochastic [9], it has recently been shown that T-bet is upregulated in lymphoid and myeloid cells by IFNγ in a Stat1-dependent manner within 6 hours, and this early T-bet activation is Stat4 independent [10].”
Background
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Background
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“IFN-γ induces the transcription factor T-box protein expressed by T cells (T-bet) [22,23].”
Background
T-bet-positive and IRTA1-positive monocytoid B cells differ from marginal zone B cells and epithelial-associated B cells in their antigen profile and topographical distribution.
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“IL-21, IL-22, IL-23R, ABCA1, ABCG1, GATA3, T-bet, IL-4, and Foxp3 have been previously described [5,26,27,28].”
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“IFNγ is a potent activator of STAT1 (Lighvani et al., 2001; Afkarian et al., 2002), whereas STAT3 is activated by a variety of cytokines, including IL6 and IL10 (Schmitz et al., 2000).”
Background
Role of Type 1 Versus Type 2 Immune Responses in Liver During the Onset of Chronic Woodchuck Hepatitis Virus Infection
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Novel ChIP-based strategies to uncover transcription factor target genes in the immune system
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“In CD4 T cells, reciprocal regulation is thought to occur by a mechanism in which IFN-gR signaling activates STAT1 and consecutively the type 1 transcription factor T-bet (19), whereas IL-4R signaling activates STAT6 and consecutively the master type 2 transcription factor GATA-3 (20); ultimately, antagonism between T…”
Background
A Genomic View of Helper T Cell Subsets
Rogge, L. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb05941.x · Cited by 36
IL-12 induced the generation of IL-21- and IFN-γ-co-expressing poly-functional CD4+ T cells from human naive CD4+ T cells
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Guadecitabine increases response to combined anti-CTLA-4 and anti-PD-1 treatment in mouse melanoma in vivo by controlling T-cells, myeloid derived suppressor and NK cells
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Recombinant Invasive Lactococcus lactis Carrying a DNA Vaccine Coding the Ag85A Antigen Increases INF-γ, IL-6, and TNF-α Cytokines after Intranasal Immunization
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Background
Lack of Ikaros Deregulates Inflammatory Gene Programs in T Cells
Ana, C. L. D., Arakcheeva, K., Agnihotri, P., Derosia, N. M., & Winandy, S. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1801270 · Cited by 32
miR-155 indicates the fate of CD4+ T cells
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“The capacity of IFN-gR signaling, but possibly not IFNAR signaling (Lighvani et al., 2001), to induce T-bet in the CD8þ T cell may indicate that IFN-g also has a unique role in differentiation.”
Peroxisome Proliferator-Activated Receptor–γ Agonist Induces Regulatory T Cells in a Murine Model of Allergic Rhinitis
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Proviral Integration Site for Moloney Murine Leukemia Virus (PIM) Kinases Promote Human T Helper 1 Cell Differentiation
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“TCR activation and STAT1 induce the expression of T box expressed in T cells (T-BET), a key transcription factor driving the Th1 polarization (8, 9).”
Background
Expression of T-bet, a type 1 T-helper cell transcription factor, in the urinary sediment of lupus patients predicts disease flare
Chan, R. W. Y., Lai, F. M.-M., Li, E. K.-M., Tam, L., Chow, K.-M., Li, P. K.-T., & Szeto, C. (2006) · Lara D. Veeken · doi:10.1093/rheumatology/kel192 · Cited by 35
“T-bet promotes Th1 lineage commitment [8, 9] and forms an autoregulatory positive feedback loop with gamma interferon to maintain Th1-mediated immune response [10].”
Background
T-bet or Not T-bet
Hatton, R. D., & Weaver, C. T. (2003) · Science · doi:10.1126/science.1092040 · Cited by 35
Ectopic T-bet Expression Licenses Dendritic Cells for IL-12-Independent Priming of Type 1 T Cells In Vitro
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Effects of Sex Steroids on Innate and Adaptive Immunity
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CD4 + T-bet + , CD4 + pSTAT3 + and CD8 + T-bet + T cells accumulate in peripheral blood during NZB treatment
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Shaping Successful and Unsuccessful CD8 T Cell Responses Following Infection
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“T-bet is induced by both IFNγ and IL-12 signaling [85, 150, 151] and is upregulated in response to inflammatory signals (Figures 3 and 4).”
A mechanism underlying STAT4-mediated up-regulation of IFN- induction inTCR-triggered T cells
Park, W.-R. (2004) · International Immunology · doi:10.1093/intimm/dxh034 · Cited by 34
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Transcriptional Programs Underlying Cd4 T Cell Differentiation and Functions
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“Th1 responses are typically driven by IL-12 and IFN-g and by the transcription factors STAT4 and T-bet (2, 3), whereas Th2 responses are driven by IL-4, IL-5, IL-13, IL-18, and IL-33 and the transcription factors STAT6, GATA3, c-maf, and NFATc (4, 5).”
BackgroundMethodInfluential
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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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