Affinage

TBX21

T-box transcription factor TBX21 · UniProt Q9UL17

Length
535 aa
Mass
58.3 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBX21 (T-bet) is a T-box transcription factor that serves as the master driver of type 1 immune programming across CD4+ Th1, CD8+ Tc1, NK, NKT, B, and innate lymphoid cell lineages (PMID:17339440, PMID:23232398, PMID:15084276). It functions by binding distal enhancers and promoters at type 1 immune genes — directly activating IFN-γ, CD122/IL-15Rβ, CXCR3, Tim-3, IL-23R, and osteopontin, and even autoactivating its own locus (PMID:17339440, PMID:23232398, PMID:20049876, PMID:17237380, PMID:16286640). Transcriptional activation proceeds through recruitment of Mediator and P-TEFb (the Super Elongation Complex) to license elongation of RNA Pol II stalled at Th1 promoters, and through recruitment of Jmjd3 (H3K27 demethylase) and Set7/9 (H3K4 methyltransferase) complexes that establish active chromatin and epigenetically imprint loci such as Ifng (PMID:27292648, PMID:20969596, PMID:30232200). In parallel, T-bet enforces lineage fidelity by repressing alternative programs: it physically engages GATA-3 in a tyrosine-kinase-dependent manner to block its DNA binding (Th2), interacts with Runx1 via Tyr304 to prevent Rorc transactivation (Th17), and inhibits NFATc2 binding at the IL-21 promoter (PMID:15662016, PMID:21151104, PMID:15684054). T-bet activity is set by both transcriptional inputs — induced by IFN-γ/STAT1 signaling and by EGR1 and Sp1, and repressed by Ikaros, c-Maf, and Egr2/3 (which bind the T-box domain to block DNA binding) — and by protein-level control through ubiquitination (NEDD4L-mediated degradation, USP10-mediated stabilization), mTORC1-dependent phosphorylation required for chromatin remodeler recruitment, and nuclear/cytoplasmic partitioning (PMID:11752460, PMID:19307156, PMID:17705132, PMID:19923223, PMID:32039762, PMID:28455436, PMID:31893939, PMID:24845384, PMID:28424242, PMID:23455505). Beyond T cells, T-bet cooperates with Eomes to govern NK and memory CD8 cell maturation and with Runx3 to program intestinal IELs, and drives B cell IgG2a/IgG2c class switching; inherited human T-bet deficiency abrogates the CD11chiCD21lo B cell subset (PMID:16273099, PMID:34521844, PMID:25148025, PMID:11960012, PMID:35867801).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2001 Medium

    Established the upstream signal that induces T-bet, defining a STAT1-dependent IFN-γ autocrine loop rather than the STAT4/IL-12 axis as the trigger for T-bet expression.

    Evidence Cytokine challenge in IFN-γ-, STAT1-, and STAT4-deficient mice with T-bet mRNA readout

    PMID:11752460

    Open questions at the time
    • Did not map the cis-elements at the Tbx21 locus mediating STAT1 responsiveness
    • Single lab, in vivo readout only
  2. 2002 High

    Extended T-bet function beyond T cells, showing it directly controls IgG2a class switching in B cells downstream of IFN-γ.

    Evidence Loss- and gain-of-function in B cells with germline transcript and isotype readouts

    PMID:11960012 PMID:12882831

    Open questions at the time
    • Direct promoter/enhancer targets at the Igh locus not mapped
    • Stimulus dependence (T-independent vs T-dependent) mechanistically unresolved
  3. 2004 High

    Demonstrated a cell-intrinsic requirement for T-bet in terminal NK and NKT maturation, broadening its role to innate lymphocytes.

    Evidence T-bet-deficient mice and bone marrow chimeras with flow cytometric maturation staging

    PMID:15084276

    Open questions at the time
    • Direct transcriptional targets driving NK maturation not defined here
    • Relationship to Eomes not addressed
  4. 2005 High

    Defined the molecular basis of lineage repression, showing T-bet blocks Th2 commitment by a tyrosine-kinase-dependent physical interaction with GATA-3 that prevents GATA-3 DNA binding.

    Evidence Co-IP, GATA-3 DNA-binding assays, and phospho-mutant analysis

    PMID:15662016

    Open questions at the time
    • The responsible tyrosine kinase not identified
    • Stoichiometry and genomic locations of the interaction unresolved
  5. 2005 High

    Identified T-bet's role in coupling effector function to migration and survival, regulating CXCR3/PSGL-1-mediated trafficking, osteopontin-driven polarization, IL-21 repression, and (with Eomes) CD122/IL-15 responsiveness.

    Evidence T-bet-deficient mice, trafficking and binding assays, promoter studies, and T-bet/Eomes compound mutants

    PMID:15684054 PMID:16014561 PMID:16273099 PMID:16286640

    Open questions at the time
    • Direct vs indirect target status not resolved for all genes in these studies
    • Division of labor between T-bet and Eomes at shared targets unmapped
  6. 2007 High

    Distinguished direct from indirect T-bet targets using temporal control, confirming IFN-γ, CD122, CXCR3, and IL-23R as acutely T-bet-regulated genes.

    Evidence Inducible T-bet-ER fusion with 4-OHT and gene expression timecourse; siRNA knockdown in EAE for IL-23R

    PMID:17237380 PMID:17339440

    Open questions at the time
    • Did not resolve enhancer vs promoter binding genome-wide
    • Cofactor requirements for acute activation not addressed
  7. 2007 Medium

    Identified the transcriptional activators of T-bet itself, showing EGR1 and Sp1 bind the human T-BET promoter to induce its expression.

    Evidence EMSA, promoter reporter assays, gain/loss-of-function, and Sp1 pharmacological inhibition

    PMID:17705132 PMID:19307156

    Open questions at the time
    • Integration with STAT1/TCR signaling at the promoter not fully resolved
    • Single lab per factor
  8. 2009 Medium

    Identified Ikaros as a direct repressor of the Tbx21 promoter in Th2 cells, establishing transcriptional gating of T-bet during lineage choice.

    Evidence ChIP at the endogenous tbx21 promoter, Ikaros dominant-negative, and in vivo infection

    PMID:19923223

    Open questions at the time
    • Mechanism of Ikaros recruitment and corepressor partners unknown
    • Single lab
  9. 2010 High

    Defined the chromatin-modifying machinery T-bet uses, showing recruitment of Jmjd3 (H3K27 demethylase) and Set7/9 (H3K4 methyltransferase) complexes, and refined repression mechanism via Runx1/Tyr304 and counter-regulation via Tim-3.

    Evidence Co-IP of T-bet with histone modifiers, histone modification mapping, Runx1 Co-IP/Y304 mutagenesis, and Tim-3 promoter analysis

    PMID:20049876 PMID:20969596 PMID:21151104 PMID:21182077

    Open questions at the time
    • Stoichiometry and genome-wide distribution of T-bet/Jmjd3/Set7-9 complexes not mapped
    • How phosphorylation gates these interactions not yet linked
  10. 2012 High

    Provided the genome-wide enhancer logic, showing T-bet and GATA3 co-occupy distal regulatory elements, T-bet autoactivates its locus, and T-bet redirects GATA3 binding.

    Evidence ChIP-seq for T-bet and GATA3, enhancer reporter assays, and sufficiency experiments

    PMID:23232398

    Open questions at the time
    • Functional consequence of every co-bound enhancer not validated
    • Mechanism of GATA3 redistribution unresolved
  11. 2016 High

    Resolved the activation mechanism at the level of Pol II, showing T-bet recruits Mediator and P-TEFb/SEC to release stalled polymerase and drive elongation and enhancer RNA transcription.

    Evidence ChIP for T-bet/Mediator/P-TEFb, knockdowns, P-TEFb pharmacological inhibition, and an EAU model

    PMID:27292648

    Open questions at the time
    • Direct contact surface between T-bet and SEC components not defined
    • How elongation control integrates with chromatin remodeling unresolved
  12. 2017 High

    Established post-translational control of T-bet, identifying NEDD4L-mediated degradation, USP10-mediated stabilization, mTORC1-dependent phosphorylation required for remodeler recruitment, and Egr2/3 as T-box-domain DNA-binding blockers.

    Evidence Ubiquitination assays, Co-IP, MRM-MS phosphosite mapping, phospho/site mutagenesis, and genetic loss-of-function with ChIP and functional readouts

    PMID:24845384 PMID:28424242 PMID:28455436 PMID:31893939

    Open questions at the time
    • Specific phosphosites linked to specific remodeler interactions not fully mapped
    • Crosstalk between ubiquitination, phosphorylation, and localization not integrated
  13. 2017 High

    Distinguished the role of T-bet expression from the presence of T-bet+ cells, showing T-bet+ Treg cells are an essential suppressive population restraining type 1 autoimmunity.

    Evidence Conditional ablation of T-bet+ Treg cells vs selective T-bet deletion, adoptive transfer, and lineage tracing

    PMID:28607488

    Open questions at the time
    • Transcriptional targets enabling Treg suppressive function not defined
    • Mechanism of co-localization with effector cells unresolved
  14. 2018 High

    Demonstrated epigenetic memory, showing transient T-bet expression imprints the Ifng locus to license later IFN-γ production in 'ex-T-bet' Tfh cells.

    Evidence T-bet fate-mapping, DNase I hypersensitivity at Ifng, and late conditional deletion

    PMID:30232200

    Open questions at the time
    • Molecular basis of heritable chromatin mark not identified
    • Reversibility and durability of imprinting unresolved
  15. 2021 High

    Dissected the T-bet/Eomes division of labor in NK biology and lineage fidelity, showing largely distinct yet overlapping programs, suppression of alternative ILC fates, and developmental control of ILC differentiation.

    Evidence Endogenous-tag ChIP-seq/RNA-seq/ATAC-seq, CRISPR deletion in primary human NK cells, ectopic expression in progenitors, and conditional/epistasis mouse models

    PMID:32039762 PMID:34521844 PMID:34556887 PMID:34630413 PMID:37279078

    Open questions at the time
    • Direct mechanistic basis for repressing RORC/AHR ILC programs not fully defined
    • Quantitative rules for T-bet vs Eomes target selection unresolved
  16. 2022 High

    Defined human disease relevance and tissue-specific roles, showing inherited T-bet deficiency abrogates CD11chiCD21lo B cells, and T-bet drives Th17-to-Th1 plasticity and adipose B cell IgG-mediated metabolic inflammation.

    Evidence Patient with inherited T-bet deficiency with ATAC-seq, conditional B/Th17 knockouts, fate-mapping, scRNA-seq, and IgG transfer experiments

    PMID:25148025 PMID:35446923 PMID:35867801 PMID:35868310

    Open questions at the time
    • Full spectrum of human T-bet-deficiency phenotypes not enumerated
    • Direct targets driving each tissue-specific program incompletely mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How T-bet's distinct post-translational modifications (phosphorylation, ubiquitination), localization control, and chromatin-modifier recruitment are mechanistically integrated to select context-specific target genes remains unresolved.
  • No structural model of T-bet bound to its remodeler or SEC partners
  • Rules governing T-bet vs Eomes target partitioning incompletely defined
  • Direct contact surfaces for repressive interactions (GATA-3, Runx1, Egr2/3) not structurally resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0098772 molecular function regulator activity 4 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 3
Partners
EGR2EOMESGATA3JMJD3NEDD4LRUNX1SET7USP10

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 T-bet induction by IFN-γ is dependent on STAT1 but not STAT4, establishing that IFN-γ drives T-bet expression through a STAT1-mediated autocrine loop that promotes further IFN-γ production. In vivo cytokine challenge with Toxoplasma gondii extract in IFN-γ-deficient and STAT1/STAT4-deficient mice; T-bet mRNA measurement Proceedings of the National Academy of Sciences of the United States of America Medium 11752460
2005 T-bet represses Th2 lineage commitment through a tyrosine kinase-mediated physical interaction with GATA-3 that interferes with GATA-3 binding to its target DNA. Co-immunoprecipitation of T-bet and GATA-3; GATA-3 DNA-binding assays; T-bet tyrosine phosphorylation mutant analysis Science (New York, N.Y.) High 15662016
2010 T-bet suppresses Th17 differentiation by physically interacting with Runx1 via T-bet Tyr304, blocking Runx1-mediated transactivation of Rorc (encoding RORγt). Co-immunoprecipitation of T-bet and Runx1; Rorc promoter transactivation assays; T-bet Y304 mutagenesis; T-bet-deficient mouse Th17 differentiation assays Nature immunology High 21151104
2005 T-bet and eomesodermin cooperatively induce CD122 (IL-15Rβ) expression, linking memory CD8+ T cell long-term renewal to cytotoxic effector programming; compound T-bet/Eomes deficiency abolishes IL-15-dependent lymphocyte lineages including memory CD8+ T cells and mature NK cells. Compound T-bet/Eomes double-mutant mice; flow cytometric enumeration of lymphocyte populations; CD122 expression analysis Nature immunology High 16273099
2004 T-bet is required in a stem cell-intrinsic manner for terminal maturation of NK cells and Vα14i NKT cells; T-bet expression in NK cells is regulated by NK-activating receptors and cytokines controlling NK development. T-bet-deficient mouse analysis; bone marrow chimera experiments establishing stem cell-intrinsic defect; flow cytometric characterization of NK/NKT maturation stages Immunity High 15084276
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-γ, and enforced T-bet expression initiates IgG2a switching in cell lines and primary cells. T-bet-deficient mouse B cell analysis; germline transcript RT-PCR; enforced T-bet expression in cell lines and primary B cells; isotype analysis by ELISA 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) stimuli but not T-dependent (CD40) stimuli in B cells. T-bet-deficient B cell stimulation with LPS (T-independent) vs. CD40 ligation (T-dependent); germline IgG2a transcript analysis; isotype switching assays International immunology Medium 12882831
2005 T-bet controls Th1 cell migration to inflammatory sites by regulating PSGL-1-mediated binding to P-selectin on inflamed endothelium and by driving expression of the chemokine receptor CXCR3. T-bet-deficient mouse in vivo T cell trafficking assays; P-selectin binding assays; CXCR3 expression analysis by flow cytometry Blood High 16014561
2005 T-bet-dependent expression of osteopontin (Opn) in activated T cells is essential for efficient skewing of CD4+ and CD8+ T cells toward Th1 and Tc1 programs; this regulation is T cell-specific and does not occur in macrophages. T-bet-deficient mouse T cell and macrophage analysis; Opn promoter studies; cytokine polarization assays Proceedings of the National Academy of Sciences of the United States of America Medium 16286640
2005 T-bet represses IL-21 transcription in Th1 cells by inhibiting the binding of NFATc2 to the IL-21 proximal promoter, which in Th2 cells activates IL-21 transcription. IL-21 promoter activity assays; NFATc2 DNA-binding assays in presence/absence of T-bet; T helper subset-specific expression analysis Proceedings of the National Academy of Sciences of the United States of America Medium 15684054
2007 IFN-γ, CD122, and CXCR3 are direct gene targets of T-bet whose expression is acutely and directly regulated by T-bet activity, demonstrated by temporally controlled inducible T-bet system. Inducible T-bet-estrogen receptor fusion protein system with 4-hydroxytamoxifen; temporal on/off control of T-bet activity with gene expression readouts Journal of immunology (Baltimore, Md. : 1950) High 17339440
2009 Ikaros directly represses the tbx21 (T-bet) promoter in Th2 cells by binding to it; loss of Ikaros DNA-binding activity during Th2 polarization results in increased T-bet expression and IFN-γ production. ChIP of Ikaros at endogenous tbx21 promoter in Th1 vs Th2 cells; Ikaros dominant-negative overexpression; in vivo parasite infection model The Journal of biological chemistry Medium 19923223
2009 EGR1 binds to the human T-BET promoter and induces T-bet transcription; EGR1 overexpression transactivates T-bet and synergizes with TCR signaling to induce T-bet expression, while EGR1 depletion decreases T-bet induction. Promoter reporter assays; EMSA demonstrating EGR1 binding to T-BET promoter; EGR1 overexpression and knockdown with T-bet expression readouts Clinical immunology (Orlando, Fla.) Medium 19307156
2007 Sp1 binds to six conserved sites in the proximal human T-BET promoter and positively regulates T-BET transcription; Sp1 overexpression increases T-BET expression and IFN-γ secretion in NK and T cells, while mithramycin A (Sp1 inhibitor) reduces both. EMSA demonstrating Sp1 binding to T-BET promoter; Sp1 overexpression; mithramycin A treatment of primary NK cells; dose-response promoter activity assays European journal of immunology Medium 17705132
2010 T-bet promotes short-lived effector CD8+ T cell differentiation over central memory formation by directly inducing CD122 and IL-15Rα expression (switching survival cytokine dependence from IL-7 to IL-15), downregulating CD127 and SOCS-1, and promoting IFN-γ and Fas ligand expression; ectopic T-bet expression plus high IL-2 drives Blimp-1 expression for terminal differentiation. In vitro ectopic T-bet expression in OT-I CD8+ T cells without inflammatory cytokines; gene expression analysis; IL-2 dose-response experiments European journal of immunology Medium 21182077
2010 T-bet regulates Tim-3 expression in Th1 cells; Tim-3 is a direct transcriptional target of T-bet, establishing a feedback loop whereby T-bet drives effector Th1 differentiation while simultaneously inducing a counter-regulatory molecule to terminate Th1 responses. T-bet-deficient mouse analysis; Tim-3 promoter studies; analysis of Th1-specific transcription factor requirements for Tim-3 expression European journal of immunology Medium 20049876
2010 T-bet recruits epigenetic modifying complexes to target genes, specifically a Jmjd3 H3K27-demethylase and a Set7/9 H3K4-methyltransferase complex, enabling reversal of repressive and establishment of active epigenetic states at Th1 target loci. Co-immunoprecipitation of T-bet with Jmjd3 and Set7/9 complexes; histone modification analysis at T-bet target genes; chromatin studies Immunological reviews Medium 20969596
2012 T-bet and GATA3 bind to multiple distal regulatory elements (enhancers) at immune regulatory genes in human effector T cells; T-bet directly activates its own expression by binding distal sites at the Tbx21 locus; T-bet is sufficient to induce GATA3 binding at T-bet target sites in Th1 cells. ChIP-seq for T-bet and GATA3 genome-wide; enhancer reporter assays; histone modification mapping; T-bet sufficiency experiments for GATA3 redistribution Nature communications High 23232398
2013 T-bet subcellular localization in human CD8+ T cells is regulated by T-bet protein levels: T-bethi cells show predominantly nuclear T-bet, while T-betlo cells show predominantly cytoplasmic T-bet; TCR stimulation rapidly redistributes T-bet (but not Eomes) to the nucleus across all memory populations within 24 hours. Multiparameter flow cytometry with nuclear/cytoplasmic fractionation; TCR stimulation timecourse; analysis across human CD8 T cell memory subsets Journal of immunology (Baltimore, Md. : 1950) Medium 23455505
2014 In intestinal intraepithelial lymphocytes (IELs), T-bet cooperates with Runx3 to suppress conventional CD4+ Th functions and induce IEL-specific programming including CD8αα homodimer expression; IFN-γ sensing and T-bet expression are both required for this IEL maturation program. Gene loss- and gain-of-function in T cells; reporter mouse strains; analysis of IEL marker expression and CD4 Th function suppression Immunity Medium 25148025
2014 USP10 interacts with T-bet in the nucleus, directly inhibits T-bet ubiquitination, and stabilizes T-bet protein; Quercetin (a T-bet inhibitor) targets USP10 to promote T-bet proteasomal degradation. Co-immunoprecipitation of USP10 and T-bet; ubiquitination assays; USP10 overexpression with T-bet stability readout; proteasome inhibitor experiments; Quercetin treatment Biochemical and biophysical research communications Medium 24845384
2015 ST2 (IL-33 receptor) expression on Th1 effector cells depends on T-bet and STAT4; T-bet-dependent ST2 expression allows IL-33 to act as a direct cofactor driving antiviral Th1 effector cell activation, expansion, and cytokine production. T-bet-deficient mouse analysis; mixed bone marrow chimeras; adoptive cell transfer; in vitro Th1 differentiation assays Proceedings of the National Academy of Sciences of the United States of America Medium 25829541
2016 T-bet activates Th1 genes through enhancers by recruiting Mediator and P-TEFb (as part of the Super Elongation Complex), enabling transcriptional elongation of RNA polymerase II already stalled at Th1 gene promoters in Th2 cells; T-bet also activates enhancer RNA transcription via P-TEFb. ChIP for T-bet, Mediator, P-TEFb at Th1 gene loci; P-TEFb pharmacological inhibition; Mediator and SEC knockdown; Pol II occupancy analysis; P-TEFb inhibition in experimental autoimmune uveitis model Cell reports High 27292648
2017 mTORC1 signaling controls T-bet phosphorylation at multiple sites in CD4+ T cells; mTORC1-dependent phosphorylation of T-bet is required for efficient recruitment of chromatin remodeling complexes to the Ifng gene promoter and IFN-γ expression. Targeted mass spectrometry (MRM-MS) identification of T-bet phosphorylation sites; Rheb-deficient CD4+ T cells; rapamycin treatment; alanine mutagenesis of phosphorylation sites; ChIP for chromatin remodeling complex recruitment Journal of immunology (Baltimore, Md. : 1950) High 28424242
2017 NEDD4L mediates ubiquitination and proteasomal degradation of T-bet in CD4+ T cells; the PKA/phospho-Sp1/NEDD4L pathway downstream of the prostaglandin D2/DP1 axis controls T-bet stability and Th1 cytokine production. T-bet ubiquitination assays; NEDD4L overexpression and deletion; T-bet conditional knockout in CD4+ T cells; Western blot for T-bet protein levels; hypertension model Circulation Medium 31893939
2017 Egr2 and Egr3 physically interact with the T-box domain of T-bet and block T-bet DNA binding, thereby inhibiting T-bet-mediated IFN-γ production in CD4+ and CD8+ effector T cells. Co-immunoprecipitation of Egr2/3 with T-bet; T-bet DNA-binding assays in presence of Egr2/3; Egr2/3-deficient T cells; Th1/Th17 differentiation assays; viral infection model Journal of immunology (Baltimore, Md. : 1950) High 28455436
2017 T-bet+ Treg cells have an essential immunosuppressive function; loss of T-bet-expressing Treg cells (but not T-bet expression within Treg cells) causes severe Th1 autoimmunity; T-bet+ Treg cells specifically co-localize with and inhibit T-bet+ effector T cells and CD8 T cell activation. Conditional ablation of T-bet-expressing Treg cells vs. selective T-bet deletion within Treg cells; adoptive transfer; lineage tracing; infection models in mice Nature High 28607488
2021 EOMES and T-BET regulate largely distinct gene sets during NK cell development: EOMES is dominant in immature NK cells and drives early lineage specification, while T-BET is dominant in mature NK cells where it induces IL-12 responsiveness and represses the cell cycle; both TFs show strong overlap in DNA binding targets with extensive epigenetic changes during differentiation. Gene-modified mice with endogenous ChIP tags for EOMES and T-BET; ChIP-seq; RNA-seq; ATAC-seq; conditional knockout models Nature communications High 34521844
2021 Human T-bet governs the differentiation of CD11chiCD21lo B cells by controlling chromatin accessibility at lineage-defining genes including FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, and CXCR4; inherited T-bet deficiency abrogates this B cell subset in vivo and in vitro. Patient with inherited T-bet deficiency; in vitro B cell differentiation assays; ATAC-seq for chromatin accessibility; flow cytometry; in vivo B cell subset analysis Science immunology High 35867801
2021 T-BET and EOMES in primary human NK cells are required for normal NK cell proliferation, persistence in vivo, cytokine responses, and antitumor function; deletion of these TFs causes CD56bright NK cells to acquire an ILC precursor-like profile with increased RORC and AHR, revealing T-box TF roles in suppressing alternative ILC lineages. CRISPR/Cas9 deletion of T-BET and EOMES in primary human NK cells; in vivo antitumor xenograft model; single-cell RNA-seq; cytokine stimulation assays The Journal of clinical investigation High 37279078
2021 T-BET and EOMES ectopically expressed in human hematopoietic progenitors epigenetically repress HSC quiescence and non-NK lineage genes while activating NK-specific transcriptome; T-BET specifically controls terminal maturation markers and KIR expression epigenetically, while EOMES shows superior early NK maturation and CD16 induction. Ectopic T-BET or EOMES expression in human hematopoietic progenitor cells; transcriptome, ATAC-seq, and protein expression analyses; NK cell functional assays Frontiers in immunology High 34630413
2018 Transient T-bet expression epigenetically imprints the Ifng locus in Tfh cells, partially opening chromatin accessibility at the locus and enabling IFN-γ production in an 'ex-T-bet' Tfh subset; IFN-γ-expressing Tfh cells are absent in T-bet-deficient mice but present when T-bet is deleted only at late T cell differentiation stages. T-bet fate-mapping mouse strains; DNase I hypersensitivity analysis of Ifng locus; multicolor tissue imaging; T-bet conditional late-deletion mice The Journal of experimental medicine High 30232200
2021 T-bet deletion during embryogenesis rescues lymph node formation in RORγt-deficient mice by skewing fetal ILC differentiation fate; mechanistically, T-bet deletion promotes accumulation of PLZFhi ILC progenitors expressing LTi molecules in a RORα-dependent fashion. Multiple conditional mouse models; single-cell analysis of fetal ILCs and ILC progenitors; T-bet/RORγt double-deficient mice; RORα genetic interaction experiments Nature immunology High 34556887
2007 T-bet directly regulates transcription of the IL-23R in CD4+ T cells, thereby influencing the fate of Th17 cells which depend on IL-23 signaling for survival. T-bet siRNA knockdown in EAE model; IL-23R expression analysis in T-bet-deficient cells; therapeutic siRNA administration with clinical and cellular readouts Journal of immunology (Baltimore, Md. : 1950) Medium 17237380
2022 T-bet in B cells drives IgG2c class switching and promotes IFN-γ and inflammatory macrophage accumulation in adipose tissue; T-bet-derived IgG from adipose B cells is a key mediator of metabolic inflammation in obesity, as confirmed by serum/IgG transfer experiments. B cell-specific Tbx21 knockout mice; B cell transfer experiments; serum and purified IgG transfer from HFD mice to T-bet+ B cell-deficient mice; cytokine and metabolic measurements Cell metabolism High 35868310
2022 T-bet expression in Th17 cells (via Tbx21-flox x Il17aCre) is required for Th17-to-Th1 transdifferentiation plasticity; blocking this transdifferentiation increases S. aureus tissue loads in a sepsis model. Conditional T-bet knockout in Th17 fate cells (Il17aCre x Tbx21-flox); Il17aCre x R26YFP fate-mapping; single-cell RNA-seq of renal Th17 fate cells; S. aureus sepsis model PLoS pathogens High 35446923
2020 c-Maf directly restrains T-bet expression in CCR6− ILC3s; conversely, c-Maf expression is dependent on T-bet, forming a negative feedback loop that preserves ILC3 identity by limiting T-bet-driven type 1 differentiation. c-Maf-deficient mouse phenotypic and transcriptomic profiling; direct c-Maf occupancy at T-bet locus; cytokine regulation of c-Maf and T-bet eLife Medium 32039762

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nature immunology 1043 16273099
2004 T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. Immunity 595 15084276
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 569 11752460
2005 T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science (New York, N.Y.) 401 15662016
2013 T-bet: a bridge between innate and adaptive immunity. Nature reviews. Immunology 399 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
2017 Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 332 28607488
2010 T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nature immunology 314 21151104
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 T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nature communications 279 23232398
2009 T-bet is essential for encephalitogenicity of both Th1 and Th17 cells. The Journal of experimental medicine 226 19546248
2007 T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity. Journal of immunology (Baltimore, Md. : 1950) 210 17237380
2005 T-bet is required for optimal proinflammatory CD4+ T-cell trafficking. Blood 207 16014561
2011 T-bet in disease. Nature immunology 200 21685955
2014 Characterization of T-bet and eomes in peripheral human immune cells. Frontiers in immunology 167 24860576
2015 T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses. Proceedings of the National Academy of Sciences of the United States of America 152 25829541
2010 T-bet and eomesodermin are required for T cell-mediated antitumor immune responses. Journal of immunology (Baltimore, Md. : 1950) 151 20713880
2018 T-bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1. European journal of immunology 143 29424438
2017 Role of CD11c+ T-bet+ B cells in human health and disease. Cellular immunology 142 28756897
2005 T-bet-dependent expression of osteopontin contributes to T cell polarization. Proceedings of the National Academy of Sciences of the United States of America 129 16286640
2021 The expansion of human T-bethighCD21low B cells is T cell dependent. Science immunology 124 34623902
2017 Transcription Factor T-bet Orchestrates Lineage Development and Function in the Immune System. Trends in immunology 124 28279590
2016 CCR5+T-bet+FoxP3+ Effector CD4 T Cells Drive Atherosclerosis. Circulation research 123 27021296
2005 Expression of T-bet by CD4 T cells is essential for resistance to Salmonella infection. Journal of immunology (Baltimore, Md. : 1950) 123 16177105
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 112 25148025
2017 STAT4 and T-bet control follicular helper T cell development in viral infections. The Journal of experimental medicine 111 29212666
2016 T-bet and Eomesodermin in NK Cell Development, Maturation, and Function. Frontiers in immunology 110 27379101
2013 Differential localization of T-bet and Eomes in CD8 T cell memory populations. Journal of immunology (Baltimore, Md. : 1950) 109 23455505
2003 T-bet regulates T-independent IgG2a class switching. International immunology 106 12882831
2010 T-bet, a Th1 transcription factor regulates the expression of Tim-3. European journal of immunology 93 20049876
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 90 27872297
2021 Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells. Nature communications 83 34521844
2019 Induction of brain-infiltrating T-bet-expressing B cells in multiple sclerosis. Annals of neurology 82 31136008
2018 Transient T-bet expression functionally specifies a distinct T follicular helper subset. The Journal of experimental medicine 76 30232200
2006 The T-box transcription factor T-bet in immunity and autoimmunity. Cellular & molecular immunology 72 16696895
2022 T-bet+ B cells accumulate in adipose tissue and exacerbate metabolic disorder during obesity. Cell metabolism 71 35868310
2022 Human T-bet governs the generation of a distinct subset of CD11chighCD21low B cells. Science immunology 69 35867801
2017 Plasmodium DNA-mediated TLR9 activation of T-bet+ B cells contributes to autoimmune anaemia during malaria. Nature communications 69 29101363
2005 NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proceedings of the National Academy of Sciences of the United States of America 68 15684054
2010 Molecular mechanisms by which T-bet regulates T-helper cell commitment. Immunological reviews 64 20969596
2002 Developmental expression of the T-box transcription factor T-bet/Tbx21 during mouse embryogenesis. Mechanisms of development 64 12128215
2019 The evolving role of T-bet in resistance to infection. Nature reviews. Immunology 63 30846856
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
2018 T-bet deficiency attenuates cardiac remodelling in rats. Basic research in cardiology 57 29564567
2017 Aging effects on T-bet expression in human B cell subsets. Cellular immunology 57 28457482
2016 T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell reports 54 27292648
2014 TLR7, IFNγ, and T-bet: their roles in the development of ABCs in female-biased autoimmunity. Cellular immunology 53 25541140
2009 Ikaros silences T-bet expression and interferon-gamma production during T helper 2 differentiation. The Journal of biological chemistry 53 19923223
2023 T-BET and EOMES sustain mature human NK cell identity and antitumor function. The Journal of clinical investigation 49 37279078
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
2009 T-bet expression is regulated by EGR1-mediated signaling in activated T cells. Clinical immunology (Orlando, Fla.) 47 19307156
2014 The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. Journal of immunology research 46 24901011
2010 FoxP3, GATA-3 and T-bet expression in elderly asthma. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 46 21114556
2017 Signals that drive T-bet expression in B cells. Cellular immunology 45 28923237
2009 TBX21 gene variants increase childhood asthma risk in combination with HLX1 variants. The Journal of allergy and clinical immunology 45 19362357
2011 T-bet employs diverse regulatory mechanisms to repress transcription. Trends in immunology 44 22133865
2021 T-BET and EOMES Accelerate and Enhance Functional Differentiation of Human Natural Killer Cells. Frontiers in immunology 43 34630413
2014 Deubiquitination and stabilization of T-bet by USP10. Biochemical and biophysical research communications 42 24845384
2017 mTORC1 Promotes T-bet Phosphorylation To Regulate Th1 Differentiation. Journal of immunology (Baltimore, Md. : 1950) 40 28424242
2018 High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity. JCI insight 38 29367462
2003 T-bet expression is upregulated in active Behçet's disease. The British journal of ophthalmology 38 14507763
2021 T-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation. Nature immunology 37 34556887
2018 T-bet promotes potent antitumor activity of CD4+ CAR T cells. Cancer gene therapy 37 29515240
2010 T-bet-mediated differentiation of the activated CD8+ T cell. European journal of immunology 37 21182077
2002 Asthma: T-bet--a master controller? Current biology : CB 37 12007433
2017 Eomesodermin and T-bet mark developmentally distinct human natural killer cells. JCI insight 36 28289707
2016 T-bet expression by Th cells promotes type 1 inflammation but is dispensable for colitis. Mucosal immunology 35 26883725
2019 T-bet+ B cells: A common denominator in protective and autoreactive antibody responses? Current opinion in immunology 34 30784957
2017 T-bet expressing B cells - Novel target for autoimmune therapies? Cellular immunology 34 28641866
2020 DP1 Activation Reverses Age-Related Hypertension Via NEDD4L-Mediated T-Bet Degradation in T Cells. Circulation 33 31893939
2021 High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency. The Journal of experimental medicine 32 34160550
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 T-bet+CD27+CD21- B cells poised for plasma cell differentiation during antibody-mediated rejection of kidney transplants. JCI insight 31 34032636
2021 mTORC1 and mTORC2 coordinate early NK cell development by differentially inducing E4BP4 and T-bet. Cell death and differentiation 30 33462410
2018 T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection. Mucosal immunology 30 29297501
2016 T-bet Regulates Natural Regulatory T Cell Afferent Lymphatic Migration and Suppressive Function. Journal of immunology (Baltimore, Md. : 1950) 30 26880765
2011 More than just a T-box: the role of T-bet as a possible biomarker and therapeutic target in autoimmune diseases. Immunotherapy 29 21395384
2019 CD8+T-bet+ cells as a predominant biomarker for inclusion body myositis. Autoimmunity reviews 28 30825520
2005 T-bet, a T cell-associated transcription factor, is expressed in Hodgkin's lymphoma. Human pathology 28 15712176
2022 Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib. JCI insight 27 35852869
2019 RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis-Novel Targets for Therapy? Frontiers in immunology 27 30687330
2017 Egr2 and 3 Inhibit T-bet-Mediated IFN-γ Production in T Cells. Journal of immunology (Baltimore, Md. : 1950) 27 28455436
2022 Adenosine receptor 2a agonists target mouse CD11c+T-bet+ B cells in infection and autoimmunity. Nature communications 26 35064115
2012 Overexpression of T-bet gene regulates murine autoimmune arthritis. Arthritis and rheumatism 26 21905017
2011 T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis. The European respiratory journal 26 21540308
2019 T-bet optimizes CD4 T-cell responses against influenza through CXCR3-dependent lung trafficking but not functional programming. Mucosal immunology 25 31278374
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
2014 Linking obesity with type 2 diabetes: the role of T-bet. Diabetes, metabolic syndrome and obesity : targets and therapy 24 25092994
2018 Loss of T-bet confers survival advantage to influenza-bacterial superinfection. The EMBO journal 23 30322895
2016 Expression of T-bet, Eomesodermin and GATA-3 in porcine αβ T cells. Developmental and comparative immunology 23 26920461
2020 Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is associated with IRF7, BANK1 and TBX21 polymorphisms in two populations. European journal of neurology 22 33065758
2025 T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis. Cell reports. Medicine 21 40107244
2018 Dynamic DNA Methylation Changes of Tbx21 and Rorc during Experimental Autoimmune Uveitis in Mice. Mediators of inflammation 21 30254507
2022 Th17 cell plasticity towards a T-bet-dependent Th1 phenotype is required for bacterial control in Staphylococcus aureus infection. PLoS pathogens 20 35446923
2024 T-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms. Nature communications 19 38336876

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