Affinage

TBX21

T-box transcription factor TBX21 · UniProt Q9UL17

Length
535 aa
Mass
58.3 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBX21 (T-bet) is a T-box transcription factor that serves as the master regulator of type 1 immune responses across both innate and adaptive immune compartments, governing Th1 CD4+ T cell commitment, CD8+ effector/memory fate, ILC maturation, NK cell terminal differentiation, NKT cell development, B cell IgG2a class switching, and Treg functional specialization (PMID:10761931, PMID:16357323, PMID:23334414, PMID:34521844, PMID:28607488). T-bet directly transactivates the IFN-gamma gene and additional targets including CXCR3, CD122, Tim-3, IL-23R, IL-36γ, and FUT7 by recruiting Mediator and the super elongation complex (P-TEFb/SEC) to enhancers, thereby promoting transcriptional elongation of poised genes (PMID:27292648, PMID:17339440, PMID:17075044). Its expression is induced by IFN-γ/STAT1 and IL-12/STAT4 through a distal enhancer, with additional transcriptional input from Notch1 and Sp1, post-transcriptional stabilization of its mRNA by Arid5a, and protein-level regulation through USP10-mediated deubiquitination and NEDD4L-mediated ubiquitin-dependent degradation (PMID:11752460, PMID:17575072, PMID:15991363, PMID:27671645, PMID:24845384, PMID:31893939). T-bet simultaneously represses alternative lineage programs—suppressing Th2 cytokines through antagonism of GATA-3, Th17 responses through RORγt suppression, and central-memory CD8+ differentiation through IL-7Rα repression—while its activity is modulated by physical interactions with Runx3, Egr2/3, and c-Maf (PMID:12882831, PMID:20974984, PMID:17698591, PMID:28455436, PMID:25148025, PMID:32039762).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 High

    The discovery that T-bet directly transactivates IFN-γ and redirects Th2 cells to a Th1 fate established TBX21 as the master transcription factor for Th1 lineage commitment, answering the long-standing question of what drives Th1 specification.

    Evidence Retroviral transduction of T-bet into polarized Th2/Tc2 primary T cells with cytokine and transcription assays

    PMID:10761931

    Open questions at the time
    • Genome-wide direct target repertoire not yet defined
    • Mechanism of Th2 gene repression not established
    • Role beyond T cells unknown
  2. 2001 High

    Identification that T-bet targets chromatin remodeling to individual IFN-γ alleles and induces IL-12Rβ2 expression, and that T-bet itself is induced by IFN-γ/STAT1, established the positive-feedback loop (IFN-γ → STAT1 → T-bet → IFN-γ) and placed T-bet upstream of IL-12 signaling.

    Evidence Allele-specific chromatin remodeling assays plus IFN-γ/STAT1/STAT4-deficient mice and in vivo infection models

    PMID:11397944 PMID:11752460

    Open questions at the time
    • Precise chromatin remodeling complexes recruited by T-bet not identified
    • Whether STAT4 independently regulates T-bet expression not resolved
  3. 2002 High

    Demonstration that T-bet directly regulates IgG2a class switching in B cells extended its functional role beyond T cells, establishing T-bet as a lineage-specifying factor in multiple immune compartments.

    Evidence T-bet KO B cells, retroviral overexpression, germline transcript analysis for IgG2a switching

    PMID:11960012 PMID:12882831

    Open questions at the time
    • Whether T-bet directly binds the IgG2a switch region or acts indirectly not determined
    • Relevance to human B cell class switching unconfirmed
  4. 2004 High

    ChIP demonstrated direct T-bet binding to IFN-γ and STAT1 promoters, and genetic epistasis showed T-bet is dominant over STAT1 for encephalitogenicity, resolving the hierarchy between T-bet and STAT1 in autoimmune pathogenesis.

    Evidence ChIP for T-bet on IFN-γ/STAT1 promoters; T-bet/STAT1 single and double KO mice in EAE

    PMID:15238607 PMID:15539157

    Open questions at the time
    • Mechanism by which T-bet drives pathogenicity independent of IFN-γ not identified
    • Specific T-bet cofactors at these promoters unknown
  5. 2005 High

    Notch1 was identified as a direct upstream transcriptional regulator of Tbx21, and T-bet was shown to control NKT cell maturation, broadening the upstream signaling inputs and downstream immune cell types governed by T-bet.

    Evidence Notch1 binding to Tbx21 promoter plus gamma-secretase inhibitor studies; ectopic T-bet expression in immature NKT cells with microarray profiling

    PMID:15991363 PMID:16357323

    Open questions at the time
    • Relative contributions of Notch1, STAT1, and STAT4 to T-bet induction in different cell types not quantified
    • Whether Notch-T-bet axis operates in all T-bet-expressing lineages unknown
  6. 2006 High

    Multiple studies established that T-bet controls target gene-specific programs in distinct immune compartments: CXCR3-dependent migration versus cytotoxicity in CD8+ T cells, FUT7 via antagonism of GATA-3, and DC-intrinsic cytokine production required for inflammatory arthritis.

    Evidence CXCR3 retroviral reconstitution in T-bet KO CD8+ T cells; EMSA/co-IP of T-bet-GATA3 on FUT7 promoter; adoptive transfer of T-bet+ DCs in arthritis model

    PMID:16410834 PMID:17056513 PMID:17075044

    Open questions at the time
    • Full spectrum of T-bet direct versus indirect targets in each cell type not delineated
    • Structural basis of T-bet/GATA-3 antagonism not resolved
  7. 2007 High

    A temporal dissection using inducible T-bet-ER fusion identified IFN-γ, CD122, and CXCR3 as acute direct targets, while enhancer mapping revealed a distal IL-12/STAT4- and IFN-γ/STAT1-responsive element controlling T-bet expression, defining both inputs and outputs with temporal precision.

    Evidence Tamoxifen-inducible T-bet-ER system; luciferase reporter assays with enhancer mutagenesis; Sp1 EMSA on T-bet promoter; T-bet KO CD8+ memory/effector cell analysis

    PMID:17339440 PMID:17575072 PMID:17698591 PMID:17705132

    Open questions at the time
    • Whether all acute targets represent direct DNA binding or require cofactors not fully resolved
    • Kinetic hierarchy among direct targets unknown
  8. 2009 High

    T-bet was shown to be required for encephalitogenicity of myelin-specific T cells independent of whether they produce IFN-γ or IL-17, revealing a cytokine-independent pathogenicity program controlled by T-bet.

    Evidence Adoptive transfer of Th1 or Th17 differentiated myelin-specific TCR transgenic T cells into EAE mice

    PMID:19546248

    Open questions at the time
    • Molecular effectors of this cytokine-independent T-bet pathogenicity program not identified
  9. 2010 High

    T-bet was found to directly induce Tim-3 (a Th1 counter-regulatory receptor) and to suppress Th17 responses (IL-17A/F, RORγt) through a STAT1-independent mechanism, establishing T-bet as both an activator and a self-limiting regulator of Th1 responses.

    Evidence T-bet KO/overexpression for Tim-3 analysis; ectopic T-bet in STAT1-deficient T cells for Th17 suppression

    PMID:20049876 PMID:20974984

    Open questions at the time
    • Whether Tim-3 regulation is a direct promoter event not confirmed by ChIP
    • Molecular mechanism of STAT1-independent Th17 suppression unclear
  10. 2012 High

    T-bet was established as essential for ILC biology: required cell-intrinsically for NKp46+ ILC generation and IL-22 production, and for suppressing IL-7R on ILCs to control intestinal homeostasis; its loss in innate cells drives colitis and regulates IL-36γ in myeloid cells.

    Evidence T-bet KO bone marrow chimeras for ILC analysis; TRUC (Tbx21−/−Rag2−/−) mice for colitis; T-bet KO DCs and ectopic expression in keratinocytes for IL-36γ

    PMID:23063332 PMID:23095752 PMID:23209316

    Open questions at the time
    • Graded T-bet dosage effects on ILC fate decisions not yet defined
    • Epigenetic mechanism at Tbx21 locus during ILC development not characterized
  11. 2013 High

    Graded T-bet expression was shown to control fate decisions in RORγt+ ILCs, instructing IFN-γ production and NKp46 expression for protection against Salmonella, establishing a dose-dependent model for T-bet function in innate lymphoid cells.

    Evidence T-bet KO mice with commensal manipulation, IL-23 stimulation, Salmonella infection, genetic fate-mapping

    PMID:23334414

    Open questions at the time
    • Molecular basis by which T-bet dosage is translated into distinct ILC fates not resolved
  12. 2014 High

    T-bet was found to cooperate with Runx3 to suppress conventional CD4+ T helper functions and induce the CD8αα+ intraepithelial lymphocyte program, and USP10 was identified as a deubiquitinase stabilizing T-bet protein.

    Evidence T-bet/Runx3 loss- and gain-of-function for IEL program; co-IP of USP10 with T-bet plus ubiquitination assays

    PMID:24845384 PMID:25148025

    Open questions at the time
    • Structural basis of T-bet–Runx3 cooperation not determined
    • USP10–T-bet interaction awaits independent confirmation and structural mapping
  13. 2016 High

    The elongation mechanism was resolved: T-bet activates Th1 genes by recruiting Mediator and P-TEFb/SEC to enhancers to convert poised RNA Pol II into productive elongation, independent of RelA and Brd4; T-bet mRNA was shown to be stabilized by Arid5a binding to a 3′UTR stem-loop; T-bet in Tregs drives CXCR3 expression and islet-accumulation to restrain type 1 diabetes.

    Evidence ChIP-seq/P-TEFb inhibition/Mediator knockdown; Arid5a KO mice with RNA-binding assays; Treg-specific T-bet conditional KO in NOD mice

    PMID:27292648 PMID:27671645 PMID:27872297

    Open questions at the time
    • Whether the elongation mechanism applies equally to all T-bet target loci not tested
    • Full repertoire of RNA-binding proteins regulating T-bet mRNA unknown
  14. 2017 High

    Multiple regulatory layers were defined: mTORC1-dependent phosphorylation at specific T-bet sites controls chromatin complex recruitment; Egr2/3 physically block the T-box DNA-binding domain; T-bet+ Tregs are functionally essential for suppressing Th1/CD8 responses; and B cell-intrinsic T-bet drives lupus germinal center formation.

    Evidence Mass spectrometry of T-bet phosphosites plus mutagenesis; co-IP mapping Egr2/3 to T-box domain; T-bet fate-mapping and depletion in Tregs; conditional B cell-specific T-bet deletion in lupus mice

    PMID:28240602 PMID:28424242 PMID:28455436 PMID:28607488

    Open questions at the time
    • Kinases directly phosphorylating T-bet downstream of mTORC1 not identified
    • How T-bet+ Tregs acquire distinct suppressive mechanisms versus effector T-bet+ cells not resolved
  15. 2020 Medium

    NEDD4L was identified as the E3 ligase mediating T-bet ubiquitination and degradation, and c-Maf was shown to form a negative feedback loop with T-bet in ILC3s restraining type 1 programming.

    Evidence NEDD4L overexpression and T-bet ubiquitination assays in CD4+ T cells with hypertension model; c-Maf KO ILC3 transcriptomic and chromatin analysis with T-bet epistasis

    PMID:31893939 PMID:32039762

    Open questions at the time
    • Whether NEDD4L is the sole E3 ligase for T-bet not established
    • Relative contributions of USP10 versus NEDD4L in different cell types not compared
  16. 2021 High

    Human inherited T-bet deficiency established its non-redundant roles: T-bet governs chromatin accessibility at lineage-defining loci in CD11c+CD21low B cells and is required for Th2 suppression and IgG2 class switching; EOMES and T-bet were shown to regulate largely distinct gene sets during NK maturation despite overlapping DNA binding.

    Evidence Human T-bet-deficient patient with ATAC-seq and in vitro differentiation; WT vs. mutant T-bet rescue in Th2 cells; endogenous ChIP-seq/ATAC-seq of EOMES and T-bet in NK cells; human inborn errors of immunity panel for T-bet+ B cell requirements

    PMID:34160550 PMID:34521844 PMID:34623902 PMID:35867801

    Open questions at the time
    • Full phenotypic spectrum of human T-bet deficiency not yet characterized
    • How T-bet and EOMES partition target gene regulation at shared binding sites not mechanistically resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of T-bet interactions with its diverse partner transcription factors, the complete catalog of direct T-bet targets across all expressing cell types, and the mechanisms by which graded T-bet expression produces qualitatively distinct cell fates.
  • No crystal structure of T-bet in complex with any partner or DNA
  • Genome-wide direct target maps across all T-bet-expressing lineages not available
  • Dose-dependent mechanism converting T-bet levels into distinct ILC/T cell fates not molecularly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-168256 Immune System 9 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 3
Partners
ARID5AEGR2EGR3GATA3MAFNEDD4LRUNX3USP10

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 T-bet (TBX21) directly transactivates the IFN-gamma gene and induces endogenous IFN-gamma production; retroviral transduction of T-bet into polarized Th2 and Tc2 primary T cells redirects them into Th1 and Tc1 cells, simultaneously inducing IFN-gamma and repressing IL-4 and IL-5, establishing T-bet as the master regulator of Th1 lineage commitment. Retroviral gene transduction, ectopic expression, transactivation assays in primary T cells Cell High 10761931
2001 T-bet specifies Th1 effector fate by targeting chromatin remodeling to individual IFN-gamma alleles and by inducing IL-12 receptor beta2 expression, acting upstream of IL-12/STAT4-dependent survival and trans-activation signals. Allele-specific chromatin remodeling assays, IL-12 receptor expression analysis, genetic epistasis Science High 11397944
2001 T-bet is rapidly and directly induced by IFN-gamma in a STAT1-dependent but STAT4-independent manner, establishing an autocrine loop whereby IFN-gamma induces T-bet which then promotes further IFN-gamma production. In vivo infection model (Toxoplasma gondii), IFN-gamma-deficient and STAT1-deficient mice, cytokine stimulation of naive T cells and myeloid cells Proceedings of the National Academy of Sciences of the United States of America High 11752460
2002 T-bet directly regulates IgG class switching in B cells, particularly to IgG2a; T-bet-deficient B cells cannot generate germline or post-switch IgG2a transcripts in response to IFN-gamma, and enforced T-bet expression initiates IgG2a switching in cell lines and primary cells. T-bet knockout B cells, retroviral overexpression, germline transcript analysis, in vitro class-switch assays Proceedings of the National Academy of Sciences of the United States of America High 11960012
2003 T-bet is selectively required for IgG2a class-switch recombination in response to T-independent (LPS) but not T-dependent (CD40) stimuli in B cells, identifying T-bet as a class-specific regulator of B cell differentiation. T-bet-deficient B cell assays with T-independent (LPS) and T-dependent (CD40) stimuli, germline transcript analysis International immunology High 12882831
2004 T-bet binds directly to the IFN-gamma and STAT1 promoters to regulate their transcription; T-bet-specific antisense oligonucleotides and siRNA suppress T-bet, IFN-gamma, and STAT1 during antigen-specific T cell differentiation, but T-bet does not regulate the IL-12/STAT4 pathway. Chromatin immunoprecipitation (T-bet binding to IFNg and STAT1 promoters), siRNA/antisense knockdown, in vitro T cell differentiation assays Immunity High 15539157
2004 T-bet function is dominant over STAT1 in EAE: T-bet-deficient mice are resistant to EAE while STAT1-deficient mice are highly susceptible; double T-bet/STAT1 knockout mice are protected, establishing T-bet as the critical downstream effector for Th1-mediated encephalitogenicity. Genetic epistasis using T-bet KO, STAT1 KO, and double KO mice in EAE model; TCR transgenic crosses The Journal of experimental medicine High 15238607
2005 Notch1 directly regulates Tbx21 transcription through complexes formed on the Tbx21 promoter; gamma-secretase inhibitors block Notch processing and extinguish T-bet and IFN-gamma expression in Th1 cells, while ectopic activated Notch1 restores Tbx21 transcription. Promoter complex analysis (Notch1 on Tbx21 promoter), gamma-secretase inhibitor treatment, ectopic Notch1 expression, EAE in vivo model Nature immunology High 15991363
2005 T-bet controls migration, survival, and effector functions of Valpha14i NKT cells; ectopic T-bet expression in immature NKT cells is sufficient to drive maturation by inducing Th1-associated cytokines, chemokines, chemokine receptors, and molecules involved in cytolysis. Microarray gene-expression analysis, in vitro ectopic T-bet expression in immature NKT cells, developmental analysis in T-bet KO mice Blood High 16357323
2006 T-bet in dendritic cells is essential for inflammatory arthritis: T-bet regulates IL-1alpha, MIP-1alpha, and TARC production by DCs and is required for T helper cell activation; adoptive transfer of T-bet-expressing DCs reconstitutes inflammation in T-bet-deficient mice. T-bet KO mice in collagen antibody-induced arthritis (CAIA), RAG2/T-bet double KO, adoptive transfer of T-bet+ DCs The Journal of clinical investigation High 16410834
2006 T-bet regulates expression of CXCR3 in CD8+ CTL; retroviral CXCR3 expression in T-bet-deficient CD8+ T cells reconstitutes their ability to infiltrate the heart but not to damage it, establishing that T-bet controls both CXCR3-dependent migration and a separate cytotoxicity program. T-bet KO mice, CXCR3 KO mice, retroviral reconstitution of CXCR3 in T-bet-deficient CD8+ T cells, myocarditis transgenic model Journal of immunology High 17056513
2006 T-bet regulates T-independent IgG2a class switching through a pathway that can be bypassed by T-dependent CD40 signaling; T-bet-deficient B cells have normal switching to other IgG isotypes. T-bet KO B cells stimulated with LPS (T-independent) vs. CD40 ligation (T-dependent), germline transcript analysis International immunology High 12882831
2006 GATA-3 and T-bet form a transcription factor complex that reciprocally regulates FUT7 (fucosyltransferase VII) gene transcription; T-bet promotes FUT7 transcription and interferes with GATA-3 DNA binding, while GATA-3 competes with CBP/P300 binding to the N-terminus of T-bet and recruits HDAC-3/HDAC-5 to repress FUT7. EMSA (electrophoretic mobility shift assay), co-immunoprecipitation, dominant-negative GATA-3, luciferase reporter assays, ChIP Proceedings of the National Academy of Sciences of the United States of America High 17075044
2007 T-bet directly regulates transcription of the IL-23 receptor (IL-23R), influencing Th17 cell fate; siRNA-mediated T-bet silencing in vivo suppresses both Th1 autoreactive T cells and newly differentiated Th17 cells in the CNS in EAE. siRNA silencing of T-bet in vivo in EAE, IL-23R transcriptional analysis, in vitro T cell differentiation assays Journal of immunology Medium 17237380
2007 T-bet represses IL-7Ralpha transcription and drives differentiation of effector and effector-memory CD8+ T cells at the expense of central-memory cells; overexpression of T-bet in CD8+ T cells lacking CD4+ help corrects the abnormal phenotype, establishing T-bet as a molecular switch between central- and effector-memory differentiation. T-bet KO CD8+ T cells, retroviral T-bet overexpression in 'unhelped' CD8+ T cells, memory cell phenotyping The Journal of experimental medicine High 17698591
2007 T-bet directly and acutely regulates IFN-gamma, CD122 (IL-2/IL-15Rβ), and CXCR3 gene expression as direct targets; temporal control using a tamoxifen-inducible T-bet-estrogen receptor fusion established that these genes respond acutely to T-bet activity. Inducible T-bet-ER fusion protein controlled by 4-hydroxytamoxifen (tamoxifen-inducible system), gene expression assays Journal of immunology High 17339440
2007 T-bet regulates a distant, highly conserved enhancer responsive to both IL-12/STAT4 and IFN-gamma/STAT1 signals; luciferase reporter assays showed both Stat4 and Stat1 activate transcription via this enhancer, providing an IL-12/Stat4/T-bet cascade that regulates IFN-gamma in CD8+ T cells in vivo. Luciferase reporter assays with wild-type vs. mutated T-bet enhancer, ChIP for Stat4 and Stat1 binding, in vivo virus infection model Blood High 17575072
2007 T-bet suppresses dermal sclerosis through an IL-13-dependent pathway in innate immune cells; T-bet deficiency in RAG2-deficient mice (lacking T and B cells) still confers increased sensitivity to bleomycin-induced scleroderma, and overexpression of T-bet in T cells does not affect skin sclerosis, establishing the innate immune cell as the relevant compartment. T-bet KO, RAG2/T-bet double KO, T-bet transgenic overexpression in T cells, bleomycin-induced scleroderma model, cytokine measurements Proceedings of the National Academy of Sciences of the United States of America High 17307869
2009 T-bet expression is critical for encephalitogenicity of myelin-specific T cells regardless of whether they produce IFN-gamma or IL-17, indicating T-bet drives pathogenicity through a cytokine-independent pathway. Myelin-specific TCR transgenic T cells differentiated under Th1 or Th17 conditions, adoptive transfer into EAE-susceptible mice, T-bet expression analysis The Journal of experimental medicine High 19546248
2010 T-bet directly regulates Tim-3 expression on Th1 cells; T-bet-deficient Th1 cells fail to upregulate Tim-3, establishing that the Th1-specifying transcription factor also induces the counter-regulatory molecule that terminates Th1 responses. T-bet KO T cell analysis, T-bet overexpression, Tim-3 expression assays European journal of immunology Medium 20049876
2010 T-bet acts downstream of IFN-gamma and IL-27 (STAT1-activating cytokines) to suppress Th17 responses; ectopic T-bet can suppress IL-17A, IL-17F, IL-22, and RORgammaT even in STAT1-deficient T cells, establishing a STAT1-independent T-bet pathway for Th17 suppression. T-bet KO, STAT1 KO, double KO mice; ectopic T-bet expression in STAT1-deficient T cells; in vitro priming and in vivo systemic inflammation models Journal of immunology High 20974984
2012 T-bet (Tbx21) is required for generation of NKp46+ ILC22 cells in the intestinal lamina propria; absence of T-bet causes loss of NKp46+ ILC22 in a cell-intrinsic manner established by bone marrow chimera experiments, and residual NKp46+ ILC22 show reduced RORgammat expression and impaired IL-22 production. T-bet KO mice, bone marrow chimeras, competitive reconstitution experiments, flow cytometry for ILC subsets The Journal of experimental medicine High 23209316
2012 T-bet in the innate immune system suppresses IL-7R expression on ILCs to control intestinal ILC homeostasis; loss of T-bet in Tbx21(-/-)Rag2(-/-) (TRUC) mice leads to IL-17A-producing ILC-driven colitis, driven by TNF-alpha from CD103-CD11b+ dendritic cells synergizing with IL-23 to stimulate ILCs. TRUC mice (Tbx21(-/-)Rag2(-/-)), IL-7R blockade, cytokine measurements, Helicobacter typhlonius identification as disease trigger Immunity High 23063332
2013 In CCR6-negative RORgammat+ ILCs, graded T-bet expression controls fate decisions: T-bet instructs IFN-gamma production and NKp46 expression; T-bet-deficient mice cannot generate NKp46-expressing RORgammat+ ILCs and fail to produce IFN-gamma, resulting in impaired protection against Salmonella infection. T-bet KO mice, commensal microbiota manipulation, IL-23 stimulation, Salmonella infection model, genetic fate-mapping Nature High 23334414
2014 T-bet cooperates with Runx3 to suppress conventional CD4+ T helper functions and induce an intraepithelial lymphocyte (IEL) program including CD8alphaalpha homodimer expression; IFN-gamma sensing and T-bet expression are both required for this program. Gene loss- and gain-of-function (T-bet KO, overexpression), reporter mice, flow cytometry for IEL markers Immunity High 25148025
2016 T-bet activates Th1 genes through enhancers by recruiting Mediator and P-TEFb in the form of the super elongation complex (SEC), promoting transcriptional elongation; Th1 genes occupied by RNA Pol II in Th2 cells require T-bet-mediated P-TEFb recruitment for productive elongation. This mechanism is independent of NF-kappaB RelA and Brd4. ChIP-seq, P-TEFb inhibition, Mediator/SEC knockdown, enhancer RNA analysis, EAU model Cell reports High 27292648
2016 Arid5a, an RNA-binding protein, stabilizes T-bet mRNA by binding to a conserved stem-loop structure in the 3'UTR of T-bet; Arid5a deficiency reduces T-bet mRNA and protein levels in Th1 cells, leading to decreased IFN-gamma production. Arid5a KO mice, RNA-binding assays (3'UTR stem-loop), Th1 differentiation assays, septic shock model Proceedings of the National Academy of Sciences of the United States of America High 27671645
2017 mTORC1 promotes T-bet phosphorylation at multiple sites to regulate Th1 differentiation; targeted mass spectrometry identified six T-bet phosphorylation sites, four of which are mTORC1-dependent; simultaneous alanine mutagenesis of three mTORC1-dependent sites significantly reduced IFN-gamma expression by impairing T-bet recruitment of chromatin remodeling complexes to the Ifng promoter. Multiple reaction monitoring mass spectrometry, Rheb-deficient CD4+ T cells, rapamycin treatment, alanine mutagenesis of phosphorylation sites, ChIP Journal of immunology High 28424242
2017 Egr2 and Egr3 physically interact with the T-box domain of T-bet, blocking T-bet DNA binding and inhibiting T-bet-mediated IFN-gamma production in CD4+ and CD8+ effector T cells. Co-immunoprecipitation of Egr2/3 with T-bet T-box domain, T-bet DNA binding assays, Egr2/3 KO T cells, in vitro Th1 differentiation and virus infection model Journal of immunology High 28455436
2017 T-bet-expressing B cells (conditional T-bet deletion from B cells) drive germinal center formation and IgG autoantibody production in SLE; B cell-specific T-bet deletion impairs GC formation and mitigates kidney damage in lupus-prone mice. Conditional B cell-specific T-bet deletion, spontaneous SLE mouse models, GC and autoantibody analysis The Journal of clinical investigation High 28240602
2017 T-bet+ Treg cells become highly stable even under non-permissive conditions; loss of T-bet-expressing Treg cells (but not T-bet expression within Tregs) causes severe Th1 autoimmunity; T-bet+ Tregs specifically inhibit Th1 and CD8 T cell activation consistent with their co-localization with T-bet+ effectors. T-bet fate-mapping in Treg cells, selective depletion of T-bet+ Tregs, adoptive transfer, infection models in mice Nature High 28607488
2014 USP10, a ubiquitin-processing protease, interacts with T-bet in the nucleus and directly inhibits T-bet ubiquitination, thereby increasing T-bet protein stability; the T-bet inhibitor Quercetin targets USP10, promoting T-bet proteasomal degradation. Co-immunoprecipitation (USP10 with T-bet), overexpression assays, ubiquitination assays, proteasome inhibitor studies Biochemical and biophysical research communications Medium 24845384
2007 Sp1 is a positive transcriptional regulator of human T-BET: six Sp1-binding sites in the proximal T-BET promoter are highly conserved; EMSA demonstrates physical Sp1-promoter association; ectopic Sp1 enhances T-BET expression and cytokine-induced IFN-gamma in NK and T cells; mithramycin A blocks Sp1 binding and diminishes T-BET and IFN-gamma. EMSA, luciferase reporter assays, Sp1 overexpression, mithramycin A treatment in primary human NK cells European journal of immunology High 17705132
2012 T-bet is an innate target in myeloid cells that directly regulates IL-36gamma transcription; promoter analysis revealed a T-bet binding site enabling efficient IL-36gamma induction; ectopic T-bet expression in keratinocytes (which lack T-bet) is sufficient to mediate IL-36gamma production. siRNA knockdown + genome-wide mRNA expression, promoter analysis (T-bet binding site identification), T-bet KO dendritic cells, ectopic T-bet expression in HaCaT keratinocytes The Journal of biological chemistry High 23095752
2020 NEDD4L mediates T-bet ubiquitination and degradation in CD4+ T cells downstream of the DP1/PKA/p-Sp1/NEDD4L pathway; forced NEDD4L expression or T-bet deletion in CD4+ T cells attenuates age-related hypertension. CD4+ T cell-specific DP1 KO and T-bet KO mice, NEDD4L overexpression, T-bet ubiquitination assays, telemetric blood pressure monitoring Circulation Medium 31893939
2020 c-Maf directly restrains T-bet expression in CCR6- ILC3s and forms a negative feedback loop: T-bet induces c-Maf while c-Maf limits T-bet-driven type 1 programming; loss of c-Maf results in hyper type 1 differentiation with overexpression of ILC1/NK-related genes. c-Maf KO ILC3 phenotyping, transcriptomic profiling, chromatin analysis, genetic epistasis with T-bet eLife High 32039762
2021 EOMES and T-BET regulate largely distinct gene sets during NK cell maturation, binding to largely overlapping DNA targets; EOMES drives early lineage specification while T-BET dominates in mature NK cells inducing IL-12 responsiveness and repressing the cell cycle; extensive epigenetic changes accompany this T-BET-driven maturation. Gene-modified mice with endogenous EOMES/T-BET for ChIP, ChIP-seq, ATAC-seq, NK cell developmental analysis in KO mice Nature communications High 34521844
2021 Human T-bet governs the development of a distinct CD11c+CD21low B cell subset by controlling chromatin accessibility of lineage-defining genes (FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, CXCR4); T-bet-deficient patients lack this B cell subset and show skewed class switching to IgG1/IgG4/IgE with reduced IgG2. Patient with inherited T-bet deficiency, ATAC-seq (chromatin accessibility), in vitro B cell differentiation assays, in vivo immunoglobulin isotype analysis Science immunology High 35867801
2021 Wild-type T-bet, but not patient mutant T-bet, inhibits Th2 cytokine production (IL-4, IL-5, IL-9, IL-13) when overexpressed in Th2 cells; T-bet deficiency causes CD4+ αβ T cells to overproduce Th2 cytokines, causing eosinophilia and upper airway inflammation. Overexpression of WT vs. mutant T-bet in Th2 cells, Herpesvirus saimiri-immortalized T cells from T-bet-deficient patient, cytokine measurement, patient phenotyping The Journal of experimental medicine High 34160550
2021 Expansion of human T-bethigh CD21low B cells requires combined BCR/IFNgamma receptor costimulation and is dependent on canonical NF-kappaB, CD40, IL-21 receptor, and IFNg/STAT1 signaling; TLR signaling via MyD88/IRAK4 is not required. Expansion correlates with circulating Tfh1 and Tph cells as sources of CD40L, IL-21, and IFNgamma. In vitro differentiation with defined cytokines/TLR ligands, patients with defined inborn errors of immunity (NF-kappaB, CD40, IL-21R, IFNgR, STAT1, MyD88/IRAK4 deficiencies), flow cytometry, transcriptomic and chromatin accessibility analysis Science immunology High 34623902
2016 T-BET expression in Treg cells is required for CXCR3 expression and accumulation of Treg cells in pancreatic islets; genetic ablation of T-BET from Treg cells increases diabetes onset and penetrance in NOD mice by failing to control type 1 cytokine responses. T-BET conditional KO in Treg cells (NOD mice), CXCR3 expression analysis, insulitis scoring, cytokine measurement Proceedings of the National Academy of Sciences of the United States of America High 27872297
2011 Tbx21 locus exhibits bivalent H3K4/H3K27 trimethylation marks in Th17 cells; IL-12 stimulation removes H3K27 trimethylation at Tbx21, enabling T-bet upregulation and Th17-to-Th1 plasticity. ChIP for H3K4me3 and H3K27me3 at Tbx21, Rorc, Il17a, Ifng, Il12rb2 loci in ex vivo and in vitro Th17 cells, in vivo immunization Journal of immunology Medium 21307296
2011 Tbx21 gene is expressed in mitral and tufted cells of the olfactory bulb; a ~300 nucleotide enhancer element at ~3.0 kb upstream of the Tbx21 transcription start site is both necessary and sufficient for transgene expression in mitral and tufted cells, revealing a non-immune role for the Tbx21 locus. Transgenic mice with various lengths of Tbx21 5' upstream region fused to gapVenus reporter, promoter/enhancer deletion analysis Neural systems & circuits Medium 22330144

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2724 10761931
2013 A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells. Nature 616 23334414
2001 Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science (New York, N.Y.) 608 11397944
2001 T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proceedings of the National Academy of Sciences of the United States of America 566 11752460
2013 T-bet: a bridge between innate and adaptive immunity. Nature reviews. Immunology 396 24113868
2002 T-bet regulates IgG class switching and pathogenic autoantibody production. Proceedings of the National Academy of Sciences of the United States of America 389 11960012
2004 Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. The Journal of experimental medicine 383 15238607
2017 Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 330 28607488
2005 T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proceedings of the National Academy of Sciences of the United States of America 292 15665085
2012 The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity 285 23063332
2005 Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nature immunology 255 15991363
2007 Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells. The Journal of experimental medicine 236 17698591
2009 T-bet is essential for encephalitogenicity of both Th1 and Th17 cells. The Journal of experimental medicine 226 19546248
2017 B cells expressing the transcription factor T-bet drive lupus-like autoimmunity. The Journal of clinical investigation 224 28240602
2007 T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity. Journal of immunology (Baltimore, Md. : 1950) 210 17237380
2011 T-bet in disease. Nature immunology 199 21685955
2015 Age-Associated B Cells: A T-bet-Dependent Effector with Roles in Protective and Pathogenic Immunity. Journal of immunology (Baltimore, Md. : 1950) 198 26297793
2014 Characterization of T-bet and eomes in peripheral human immune cells. Frontiers in immunology 167 24860576
2017 T-bet+ B cells are induced by human viral infections and dominate the HIV gp140 response. JCI insight 152 28422752
2004 Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes. Immunity 151 15539157
2012 Distinct requirements for T-bet in gut innate lymphoid cells. The Journal of experimental medicine 147 23209316
2017 Role of CD11c+ T-bet+ B cells in human health and disease. Cellular immunology 142 28756897
2017 Transcription Factor T-bet Orchestrates Lineage Development and Function in the Immune System. Trends in immunology 123 28279590
2006 T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia. Blood 122 16434488
2021 The expansion of human T-bethighCD21low B cells is T cell dependent. Science immunology 120 34623902
2016 CCR5+T-bet+FoxP3+ Effector CD4 T Cells Drive Atherosclerosis. Circulation research 120 27021296
2005 T-bet concomitantly controls migration, survival, and effector functions during the development of Valpha14i NKT cells. Blood 115 16357323
2004 T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn's disease. Gut 115 15306590
2019 T-bet+ memory B cells: Generation, function, and fate. Immunological reviews 112 30874358
2014 Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation. Immunity 111 25148025
2016 T-bet and Eomesodermin in NK Cell Development, Maturation, and Function. Frontiers in immunology 110 27379101
2003 T-bet regulates T-independent IgG2a class switching. International immunology 106 12882831
2010 STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and -independent mechanisms. Journal of immunology (Baltimore, Md. : 1950) 102 20974984
2006 Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells. The Journal of clinical investigation 100 16410834
2010 T-bet, a Th1 transcription factor regulates the expression of Tim-3. European journal of immunology 93 20049876
2007 Transcription factor T-bet regulates skin sclerosis through its function in innate immunity and via IL-13. Proceedings of the National Academy of Sciences of the United States of America 91 17307869
2016 Singular role for T-BET+CXCR3+ regulatory T cells in protection from autoimmune diabetes. Proceedings of the National Academy of Sciences of the United States of America 89 27872297
2006 Transcription factors T-bet and GATA-3 regulate development of airway remodeling. American journal of respiratory and critical care medicine 88 16614350
2019 Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation. Science translational medicine 85 31776286
2021 Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells. Nature communications 78 34521844
2019 Induction of brain-infiltrating T-bet-expressing B cells in multiple sclerosis. Annals of neurology 77 31136008
2006 Interaction of GATA-3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes. Proceedings of the National Academy of Sciences of the United States of America 75 17075044
2007 Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNgamma/Stat1 signals. Blood 69 17575072
2017 Plasmodium DNA-mediated TLR9 activation of T-bet+ B cells contributes to autoimmune anaemia during malaria. Nature communications 68 29101363
2022 T-bet+ B cells accumulate in adipose tissue and exacerbate metabolic disorder during obesity. Cell metabolism 67 35868310
2005 Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Human genetics 66 15806396
2022 Human T-bet governs the generation of a distinct subset of CD11chighCD21low B cells. Science immunology 65 35867801
2019 The evolving role of T-bet in resistance to infection. Nature reviews. Immunology 63 30846856
2005 Differential transcription of Eomes and T-bet during maturation of mouse uterine natural killer cells. Journal of leukocyte biology 61 16204645
2007 Temporal dissection of T-bet functions. Journal of immunology (Baltimore, Md. : 1950) 60 17339440
2016 Expanded lung T-bet+RORγT+ CD4+ T-cells in sarcoidosis patients with a favourable disease phenotype. The European respiratory journal 59 27230441
2012 IL-36γ/IL-1F9, an innate T-bet target in myeloid cells. The Journal of biological chemistry 54 23095752
2006 T-bet controls pathogenicity of CTLs in the heart by separable effects on migration and effector activity. Journal of immunology (Baltimore, Md. : 1950) 54 17056513
2016 T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell reports 53 27292648
2016 Arid5a exacerbates IFN-γ-mediated septic shock by stabilizing T-bet mRNA. Proceedings of the National Academy of Sciences of the United States of America 52 27671645
2014 TLR7, IFNγ, and T-bet: their roles in the development of ABCs in female-biased autoimmunity. Cellular immunology 52 25541140
2017 c-Myb Regulates the T-Bet-Dependent Differentiation Program in B Cells to Coordinate Antibody Responses. Cell reports 51 28423310
2014 MBD2 regulates TH17 differentiation and experimental autoimmune encephalomyelitis by controlling the homeostasis of T-bet/Hlx axis. Journal of autoimmunity 50 24934598
2011 Epigenetic changes at Il12rb2 and Tbx21 in relation to plasticity behavior of Th17 cells. Journal of immunology (Baltimore, Md. : 1950) 50 21307296
2021 Expression Regulation and Function of T-Bet in NK Cells. Frontiers in immunology 49 34675939
2017 T-bet-expressing B cells during HIV and HCV infections. Cellular immunology 49 28739077
2014 The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease. Clinical immunology (Orlando, Fla.) 47 24495857
2013 The transcription factor T-bet regulates parasitemia and promotes pathogenesis during Plasmodium berghei ANKA murine malaria. Journal of immunology (Baltimore, Md. : 1950) 46 24078698
2006 Cutting edge: STAT1 and T-bet play distinct roles in determining outcome of visceral leishmaniasis caused by Leishmania donovani. Journal of immunology (Baltimore, Md. : 1950) 46 16785492
2017 Signals that drive T-bet expression in B cells. Cellular immunology 45 28923237
2011 Genetic visualization of the secondary olfactory pathway in Tbx21 transgenic mice. Neural systems & circuits 43 22330144
2004 Cutting edge: immunity and IFN-gamma production during Listeria monocytogenes infection in the absence of T-bet. Journal of immunology (Baltimore, Md. : 1950) 43 15528324
2021 YY1 regulation by miR-124-3p promotes Th17 cell pathogenicity through interaction with T-bet in rheumatoid arthritis. JCI insight 42 34806650
2014 KLRG1+ NK cells protect T-bet-deficient mice from pulmonary metastatic colorectal carcinoma. Journal of immunology (Baltimore, Md. : 1950) 42 24415778
2015 Diverse roles for T-bet in the effector responses required for resistance to infection. Journal of immunology (Baltimore, Md. : 1950) 41 25556247
2004 Identification of a novel type 1 diabetes susceptibility gene, T-bet. Human genetics 41 15241679
2017 mTORC1 Promotes T-bet Phosphorylation To Regulate Th1 Differentiation. Journal of immunology (Baltimore, Md. : 1950) 40 28424242
2005 IL-12 up-regulates T-bet independently of IFN-gamma in human CD4+ T cells. European journal of immunology 40 16220539
2014 Deubiquitination and stabilization of T-bet by USP10. Biochemical and biophysical research communications 39 24845384
2018 High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity. JCI insight 37 29367462
2002 Asthma: T-bet--a master controller? Current biology : CB 37 12007433
2018 T-bet promotes potent antitumor activity of CD4+ CAR T cells. Cancer gene therapy 36 29515240
2017 Eomesodermin and T-bet mark developmentally distinct human natural killer cells. JCI insight 36 28289707
2019 T-bet+ B cells: A common denominator in protective and autoreactive antibody responses? Current opinion in immunology 34 30784957
2009 pSTAT1, pSTAT3, and T-bet as markers of disease activity in chronic inflammatory demyelinating polyradiculoneuropathy. Journal of the peripheral nervous system : JPNS 33 19691533
2020 c-Maf restrains T-bet-driven programming of CCR6-negative group 3 innate lymphoid cells. eLife 32 32039762
2007 Transcriptional control of human T-BET expression: the role of Sp1. European journal of immunology 32 17705132
2021 High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency. The Journal of experimental medicine 31 34160550
2021 T-bet+CD27+CD21- B cells poised for plasma cell differentiation during antibody-mediated rejection of kidney transplants. JCI insight 30 34032636
2020 DP1 Activation Reverses Age-Related Hypertension Via NEDD4L-Mediated T-Bet Degradation in T Cells. Circulation 30 31893939
2005 Upregulation of T-bet expression in peripheral blood mononuclear cells during Vogt-Koyanagi-Harada disease. The British journal of ophthalmology 30 16234441
2021 Mass Cytometry Identifies Expansion of T-bet+ B Cells and CD206+ Monocytes in Early Multiple Sclerosis. Frontiers in immunology 29 34017332
2016 Evidence for genetic association of TBX21 and IFNG with systemic lupus erythematosus in a Chinese Han population. Scientific reports 29 26916970
2010 Lck mediates Th2 differentiation through effects on T-bet and GATA-3. Journal of immunology (Baltimore, Md. : 1950) 29 20237292
2019 CD8+T-bet+ cells as a predominant biomarker for inclusion body myositis. Autoimmunity reviews 28 30825520
2019 RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis-Novel Targets for Therapy? Frontiers in immunology 26 30687330
2018 Lack of T-bet reduces monocytic interleukin-12 formation and accelerates thrombus resolution in deep vein thrombosis. Scientific reports 26 29445199
2017 Egr2 and 3 Inhibit T-bet-Mediated IFN-γ Production in T Cells. Journal of immunology (Baltimore, Md. : 1950) 26 28455436
2012 Overexpression of T-bet gene regulates murine autoimmune arthritis. Arthritis and rheumatism 26 21905017
2002 Evolution of developmental functions by the Eomesodermin, T-brain-1, Tbx21 subfamily of T-box genes: insights from amphioxus. The Journal of experimental zoology 26 12210112
2016 T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production. The Journal of allergy and clinical immunology 25 27670243
2013 The immune cell transcription factor T-bet: A novel metabolic regulator. Adipocyte 25 24575371
2012 Morphine, but not ketamine, decreases the ratio of Th1/Th2 in CD4-positive cells through T-bet and GATA3. Inflammation 25 22160839
2014 Linking obesity with type 2 diabetes: the role of T-bet. Diabetes, metabolic syndrome and obesity : targets and therapy 24 25092994
2009 Association of TBX21 polymorphisms in a Korean population with rheumatoid arthritis. Experimental & molecular medicine 24 19287198