Affinage

TOX

Thymocyte selection-associated high mobility group box protein TOX · UniProt O94900

Length
526 aa
Mass
57.5 kDa
Annotated
2026-04-28
100 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TOX is an HMG-box transcription factor that functions as a master regulator of immune cell fate by remodeling chromatin accessibility at hundreds of genomic loci to establish and maintain lineage-specific gene programs. In the thymus, TOX is induced downstream of calcineurin signaling and is essential for CD4+ T cell, regulatory T cell, NKT cell, and innate lymphoid cell development, acting partly through ThPOK-independent mechanisms to install the full CD4 lineage transcriptional program (PMID:18195075, PMID:22021617, PMID:25915732). In the context of chronic antigen stimulation, TOX is induced by NFAT2 and sustained by signals from LAG-3 and CXCR4/JAK2/STAT3; it cooperates with TOX2 and NR4A factors in a mutual amplification loop to epigenetically program CD8+ T cell exhaustion, opening chromatin at inhibitory receptor loci (PD-1, TIM-3, TIGIT) and the Tcf7 locus while being continuously required to maintain the exhausted epigenetic state and protect against activation-induced cell death (PMID:31207603, PMID:31207604, PMID:31152140, PMID:40053604, PMID:39121847). TOX also promotes follicular helper T cell differentiation downstream of BCL6 and drives oncogenic proliferation in cutaneous T-cell lymphoma by suppressing the CDK inhibitors CDKN1B and CDKN1C (PMID:31844658, PMID:25548321).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 High

    The discovery that TOX is an HMG-box protein selectively induced in immature thymocytes by TCR signaling and that its overexpression skews CD4/CD8 lineage ratios established TOX as a novel regulator of T cell development.

    Evidence Gene chip screen followed by transgenic mouse overexpression with thymocyte phenotyping

    PMID:11850626

    Open questions at the time
    • Mechanism by which TOX alters lineage commitment was unknown
    • Loss-of-function data not yet available
    • Downstream gene targets unidentified
  2. 2004 High

    Demonstrating that TOX expression depends on calcineurin and that TOX suffices to induce CD8 gene demethylation and Runx3 upregulation linked TOX to an epigenetic mechanism of lineage specification downstream of TCR-calcineurin signaling.

    Evidence Calcineurin inhibitor treatment, TOX overexpression in thymocytes, CD8 locus methylation assay, Runx3 expression analysis in transgenic mice

    PMID:15078895

    Open questions at the time
    • Whether TOX is necessary (not just sufficient) for CD4/CD8 specification was untested
    • Direct chromatin binding sites of TOX unknown
  3. 2008 High

    Genetic ablation of TOX revealed it is essential for CD4+ T cell, Treg, and NKT cell development — resolving the necessity question — while CD8+ T cells developed normally, establishing a lineage-selective requirement.

    Evidence TOX-knockout mouse with flow cytometric thymocyte phenotyping

    PMID:18195075

    Open questions at the time
    • Whether TOX acts solely through ThPOK induction or has independent roles in CD4 programming was unresolved
    • Role in peripheral T cell function unknown
  4. 2011 High

    Epistasis experiments showed TOX has ThPOK-independent functions in installing the full CD4 lineage gene program, broadening its role beyond a single downstream target.

    Evidence Enforced ThPOK expression in TOX-KO mice with gene expression profiling of CD4 lineage markers (Id2, Foxo1, Thpok)

    PMID:22021617

    Open questions at the time
    • Direct TOX-bound genomic loci in thymocytes remained uncharacterized
    • Whether TOX regulates chromatin structure directly or via cofactors was unclear
  5. 2014 High

    Extension of TOX's developmental role to innate lymphoid cell (ILC) lineage specification and demonstration of TOX function in corticogenesis via genome-wide DamID-seq binding analysis broadened the biological scope of TOX and identified its first direct genomic targets.

    Evidence TOX-KO mouse ILC differentiation assays with transcriptome profiling; DamID-seq chromatin binding in neural progenitors with in vivo brain manipulation

    PMID:25527292 PMID:25915732

    Open questions at the time
    • Genome-wide binding sites in T cells specifically were not mapped
    • Whether neural and immune functions use shared or distinct target gene programs was unknown
  6. 2014 High

    Identification of TOX as an oncogenic driver in CTCL that suppresses CDK inhibitors CDKN1B and CDKN1C provided the first link between TOX and cancer cell-intrinsic proliferation control.

    Evidence Stable shRNA knockdown in CTCL cell lines, xenograft tumor model, genetic epistasis with CDKN1B/C rescue

    PMID:25548321

    Open questions at the time
    • Whether TOX directly binds CDKN1B/C promoters or acts indirectly was unresolved
    • Upstream regulators of TOX in CTCL were not fully defined
  7. 2019 High

    Four landmark studies simultaneously established TOX as the central transcriptional and epigenetic regulator of CD8+ T cell exhaustion: TOX is induced by calcineurin/NFAT2, becomes calcineurin-independent in a feed-forward loop with NR4A factors, remodels chromatin at inhibitory receptor loci, and is essential for exhausted T cell formation but not effector/memory differentiation.

    Evidence TOX-KO and TOX DNA-binding domain mutant mice in chronic LCMV infection and tumor models; ectopic TOX expression in effector T cells; TOX/TOX2 DKO CAR T cells; ATAC-seq chromatin profiling across all studies

    PMID:31152140 PMID:31207603 PMID:31207604 PMID:31207605

    Open questions at the time
    • Whether TOX is continuously required to maintain the exhausted state once established was unknown
    • Structural basis of TOX-chromatin interaction unresolved
    • Relative contributions of TOX vs. TOX2 in human exhaustion unclear
  8. 2019 Medium

    Identification of VEGF-A, BCL6, and GATA3 as additional upstream inducers of TOX expanded the regulatory inputs beyond calcineurin/NFAT, placing TOX at a convergence point of multiple signaling pathways in tumor microenvironment and lymphoid differentiation.

    Evidence VEGF-A treatment of T cells with in vivo validation; BCL6-dependent TFH cell TOX upregulation with miRNA epistasis; GATA3 siRNA knockdown in CTCL cells

    PMID:27345620 PMID:31704735 PMID:31844658

    Open questions at the time
    • Whether VEGF-A acts directly on TOX promoter or through intermediate factors was not established
    • GATA3→TOX link shown only in CTCL cell lines with single method
  9. 2021 High

    Inducible deletion of TOX in already-committed exhausted T cells demonstrated that continuous TOX expression is required to maintain the exhausted epigenetic landscape; TOX ablation caused apoptosis, reduced inhibitory receptors, and increased fate flexibility, establishing TOX as both an initiator and sustainer of the exhausted state.

    Evidence Inducible Cre-mediated TOX deletion in established exhausted T cells during chronic infection, ATAC-seq and gene expression profiling

    PMID:40053604

    Open questions at the time
    • Mechanism by which TOX loss triggers apoptosis not defined
    • Whether re-expression of TOX can restore the exhausted program after ablation was untested
  10. 2021 Medium

    Demonstrating that inflammatory cytokines alone (without TCR stimulation) induce TOX but that cytokine-driven PD-1 expression is TOX-independent partially decoupled the TOX-PD-1 axis and revealed pathway separability.

    Evidence Cytokine stimulation of human and mouse memory T cells with and without TOX knockout, flow cytometric analysis

    PMID:34032638

    Open questions at the time
    • Which cytokine-responsive transcription factors drive TOX-independent PD-1 was not identified
    • Relevance to chronic infection vs. tumor settings unclear
  11. 2023 High

    Identification of STAT5a as a direct antagonist of TOX that can reprogram exhausted T cells toward a durable effector/NK-like state defined a reciprocal regulatory circuit governing the exhaustion-effector fate decision.

    Evidence Constitutive Stat5a expression in T cells, orthogonal IL-2/IL-2Rβ system, ATAC-seq, tumor models with PD-L1 blockade

    PMID:38091951

    Open questions at the time
    • Whether STAT5a directly represses TOX transcription or acts post-transcriptionally was not resolved
    • Long-term durability of STAT5a-reprogrammed cells in patients unknown
  12. 2024 High

    Placing LAG-3 upstream of TOX as a sustainer of TOX expression in exhausted T cells, and CXCR4/JAK2/STAT3 as an additional upstream axis, revealed new signaling inputs that maintain the exhaustion program and represent therapeutic targets.

    Evidence LAG-3-KO chronic viral infection model with TOX expression quantification; CXCR4 blockade and KO with single-cell multiomics (RNA/TCR/ATAC-seq)

    PMID:39121847 PMID:39317187

    Open questions at the time
    • Whether LAG-3 regulates TOX transcription or protein stability is undefined
    • Whether CXCR4-STAT3 and LAG-3 pathways converge on the same TOX regulatory elements is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of TOX HMG-box interaction with chromatin, the identity of cofactors that mediate TOX-dependent chromatin remodeling in T cells, and whether pharmacological targeting of TOX can modulate exhaustion in human immunotherapy remain unresolved.
  • No crystal or cryo-EM structure of TOX HMG-box bound to nucleosomal DNA
  • Chromatin remodeling cofactors recruited by TOX in T cells not identified
  • No small-molecule modulators of TOX function reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3 GO:0042393 histone binding 1
Localization
GO:0005694 chromosome 4 GO:0005634 nucleus 3
Pathway
R-HSA-168256 Immune System 7 R-HSA-4839726 Chromatin organization 5 R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1643685 Disease 2 R-HSA-5357801 Programmed Cell Death 2
Partners
BCL6LAG3NFAT2NR4A1RUNX3STAT5ATHPOKTOX2

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 TOX is an HMG-box DNA-binding protein whose expression is upregulated by both pre-TCR and TCR activation of immature thymocytes but not by TCR activation of mature naïve T cells; transgenic overexpression of TOX in mice expands CD8+ and reduces CD4+ single positive thymocyte subpopulations by perturbing lineage commitment through reduced sensitivity to TCR-mediated signaling. Gene chip isolation of Tox, transgenic mouse overexpression, thymocyte phenotyping Nature immunology High 11850626
2004 TOX expression in double-positive thymocytes is calcineurin-dependent; TOX is sufficient to induce CD8 gene demethylation, initiate positive selection to the CD8 lineage independently of MHC-TCR interactions, and upregulate Runx3, implicating CD4 silencing. A strong TCR signal can override this TOX-mediated cell fate. Calcineurin inhibitor treatment, TOX overexpression in thymocytes, CD8 gene methylation assay, Runx3 expression analysis, transgenic mouse studies The Journal of experimental medicine High 15078895
2008 TOX is required for CD4 T cell lineage development; loss of TOX causes a severe block at the CD4loCD8lo transitional stage of positive selection, resulting in failure of CD4+ T cells, regulatory T cells, and NKT cells to develop, while functional CD8+ T cells are generated normally. TOX-deficient (knockout) mouse model, flow cytometric phenotyping of thymocyte subpopulations The Journal of experimental medicine High 18195075
2011 TOX is required to establish the full CD4+ T cell lineage gene program beyond its role in ThPOK induction; enforced ThPOK expression rescues some CD4 development in TOX-deficient mice but these cells remain defective in expression of Id2, Foxo1, and endogenous Thpok, demonstrating a ThPOK-independent role for TOX in CD4 lineage programming. TOX-deficient mouse, enforced ThPOK transgenic rescue, gene expression analysis of CD4 lineage markers Journal of immunology High 22021617
2011 TOX is a member of an evolutionarily conserved DNA-binding protein family expressed in immune-relevant cell subsets; it functions by modifying local chromatin structure and modulating formation of multi-protein complexes, with potential to regulate E protein activity during thymic development. Review synthesizing prior genetic and biochemical data on TOX family members Current opinion in immunology Medium 22209117
2014 TOX is required for the in vivo differentiation of common lymphoid progenitors into ILC-lineage restricted cells; TOX deficiency causes early defects in progenitor survival/proliferation and later ILC differentiation defects, and TOX-deficient cells fail to upregulate ILC program genes including Notch targets. TOX-deficient mouse model, in vitro ILC differentiation assays, comparative transcriptome analysis of bone marrow progenitors Nature immunology High 25915732
2014 TOX acts as a transcription factor during mammalian corticogenesis, regulated by calcineurin/NFAT signaling; DamID-seq identified TOX chromatin binding motif and downstream targets including Sox2, Tbr2, and Prox1; TOX promotes neural stem cell proliferation and neurite outgrowth of newborn neurons. DamID combined with deep sequencing (chromatin binding characterization), calcineurin/NFAT pathway analysis, in vivo brain manipulation of Tox expression The EMBO journal High 25527292
2014 Aberrant TOX overexpression in cutaneous T-cell lymphoma (CTCL) drives oncogenic growth; stable knockdown of TOX in CTCL cells promotes apoptosis, reduces cell cycle progression, and increases CDK inhibitors CDKN1B and CDKN1C; blocking CDKN1B and CDKN1C reverses the growth inhibition caused by TOX knockdown, placing TOX upstream of these CDK inhibitors. Stable shRNA knockdown in CTCL cell lines, in vitro viability/colony assays, in vivo xenograft tumor model, genetic epistasis with CDKN1B/C rescue Blood High 25548321
2018 TOX is induced in CD8+ CTLs during LCMV infection and is essential for their encephalitogenic properties in CNS autoimmunity; TOX represses activity of transcription factors Id2, TCF-1, and Notch, and reduces immune checkpoint sensitivity by restraining CD244 expression on CTLs, leading to increased CTL-mediated CNS damage. Mouse model of CNS inflammation with LCMV vs. Listeria infection, TOX expression analysis in CTLs, assessment of transcription factor targets and surface CD244 expression Immunity High 29768177
2019 TOX is a central transcriptional and epigenetic regulator of CD8+ T cell exhaustion in mice; TOX is induced by calcineurin and NFAT2 and operates in a feed-forward loop becoming calcineurin-independent in exhausted T cells; in the absence of TOX, exhausted T cells fail to form, while effector and memory T cells develop normally. TOX knockout mouse, chronic LCMV infection model, ATAC-seq epigenetic profiling, calcineurin inhibitor treatment Nature High 31207603
2019 TOX is a crucial regulator of tumour-specific T cell differentiation; TOX expression is driven by chronic TCR stimulation and NFAT activation; ectopic TOX expression in effector T cells induces a transcriptional exhaustion program; Tox deletion abrogates upregulation of inhibitory receptors (PD-1, CD39, TIM-3, CD244, TIGIT) whose chromatin remains inaccessible, but TOX-deleted TST cells remain dysfunctional with impaired persistence in tumours. Ectopic TOX expression in effector T cells, Tox conditional knockout in tumor-infiltrating T cells, ATAC-seq chromatin accessibility profiling, tumor models Nature High 31207604
2019 TOX is required for development and maintenance of exhausted T cell populations during chronic LCMV infection; removal of TOX's DNA-binding domain reduces PD-1 mRNA and protein levels and augments cytokine production, yielding more polyfunctional T cells; however, TOX-deficient exhausted T cells ultimately undergo massive decline in numbers, particularly among TCF-1+ self-renewing cells, indicating TOX is critical for their long-term maintenance and protection against activation-induced cell death. TOX DNA-binding domain deletion mouse, chronic LCMV infection, flow cytometric analysis of PD-1/cytokine production, quantification of TCF-1+ progenitor subset Nature High 31207605
2019 TOX and TOX2 cooperate with NR4A family nuclear receptors downstream of NFAT to impose the CD8+ T cell exhaustion transcriptional program; TOX and TOX2 are induced by calcium/calcineurin-NFAT signaling even without AP-1; TOX positively regulates NR4A expression and NR4A positively regulates TOX expression, forming a mutual amplification loop; combined deletion of TOX and TOX2 (DKO) in CAR T cells is more effective than single deletions in suppressing tumor growth. CAR T cell model, TOX/TOX2 double-knockout, NFAT and calcineurin inhibitor experiments, ATAC-seq chromatin accessibility, tumor suppression assays in vivo Proceedings of the National Academy of Sciences High 31152140
2019 TOX promotes persistence of antiviral CD8+ T cells and is required for programming of progenitor-like CD8+ T cells during chronic viral infection; scRNA-seq showed a TOX-containing coexpression module with higher transcriptional activity and more active histone marks in progenitor-like cells compared to memory precursor cells. Single-cell RNA-seq, ATAC-seq/histone mark profiling, TOX-deficient mouse with chronic viral infection Nature immunology High 31209400
2019 VEGF-A induces TOX expression in tumor-infiltrating T cells to drive the exhaustion-specific transcriptional program; combined PD-1 and VEGF-A blockade restores antitumor T cell functions in microsatellite stable colorectal cancer. In vitro VEGF-A treatment of T cells, ex vivo and in vivo mouse studies, combinatorial checkpoint/VEGF-A blockade experiments Science immunology Medium 31704735
2019 TOX regulates follicular helper T (TFH) cell differentiation; TOX is highly upregulated in mouse and human TFH cells in a BCL6-dependent manner, and in turn promotes expression of molecules critical for TFH cell differentiation and function; the miR-23~27~24 cluster controls TFH cells partly by targeting TOX. miR-23~27~24 cluster T cell-specific knockout/overexpression, TOX expression analysis in TFH cells, BCL6 dependence assay Science advances Medium 31844658
2019 TOX expression in cutaneous T-cell lymphoma is regulated by GATA3; GATA3 knockdown decreases TOX mRNA and protein expression in CTCL cells. siRNA knockdown of GATA3 in CTCL cell lines, qRT-PCR and western blot for TOX expression Journal of the European Academy of Dermatology and Venereology Medium 27345620
2019 In Sézary syndrome (CTCL), TOX is upregulated >7-fold and inversely correlates with RUNX3 expression; TOX siRNA knockdown rescues RUNX3 expression and reduces CTCL cell viability, placing TOX upstream of RUNX3 as a tumor suppressor pathway. siRNA-mediated TOX knockdown, qRT-PCR confirmation of TOX, RUNX3, GATA3 expression, pathway analysis Oncotarget Medium 31139323
2021 Continuous TOX expression is required for maintenance of the exhausted CD8+ T cell epigenetic fate; induced TOX ablation in already-committed exhausted T cells results in apoptotic-driven cell loss, reduced inhibitory receptor expression, decreased terminal differentiation, and greater fate flexibility toward effector-like states; epigenetic profiling revealed TOX maintains chromatin accessibility and transcriptional patterns in committed exhausted T cells. Inducible Cre-based TOX deletion in established exhausted T cells, ATAC-seq epigenetic profiling, gene expression profiling, flow cytometric phenotyping Science immunology High 40053604
2021 Inflammatory cytokines (without TCR stimulation) are sufficient to upregulate TOX expression in both human and mouse CD8+ memory T cells; TOX is not necessary for cytokine-driven expression of PD-1, indicating these pathways are at least partially separable. Cytokine treatment of isolated human and mouse memory T cells, TOX knockout cells treated with cytokines, flow cytometric measurement of TOX and PD-1 JCI insight Medium 34032638
2021 TOX is required for TOX-dependent chromatin remodeling in self-reactive CD8+ T cells persisting in the CNS; TOX remodels >400 genomic regions including the Tcf7 locus; genetic ablation of TOX in CD8+ T cells results in shortened persistence of self-reactive T cells in the inflamed CNS during autoimmunity. TOX-deficient mouse model, ATAC-seq chromatin accessibility profiling of CNS-infiltrating CD8+ T cells, mouse model of CNS autoimmunity Nature communications High 33579927
2023 STAT5a and TOX operate in a reciprocally antagonistic circuit in exhausted CD8+ T cells; constitutive Stat5a activity antagonizes TOX and rewires CD8+ T cells from exhaustion toward a durable effector/NK-like state with superior anti-tumor potential; temporal induction of Stat5 using an orthogonal IL-2:IL2Rβ pair fosters intermediate exhausted T cell accumulation and partially reprograms the epigenetic landscape of exhaustion. Constitutive Stat5a expression in T cells, orthogonal IL-2:IL2Rβ signaling system, ATAC-seq epigenetic profiling, tumor models, combined PD-L1 blockade Immunity High 38091951
2024 LAG-3 sustains TOX expression and Tex cell durability; LAG-3 deficiency reduces TOX levels in exhausted CD8+ T cells; furthermore, LAG-3 governs a circuit generating a CD94/NKG2+ subset of exhausted T cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b. LAG-3 knockout in chronic viral infection mouse model, PD-1 and/or LAG-3 blockade, flow cytometric analysis of TOX expression, CD94/NKG2 subset characterization, human parallel analysis Cell High 39121847
2024 CXCR4 orchestrates the TOX-programmed exhausted CD8+ T cell phenotype via the JAK2/STAT3 pathway; CXCR4 blockade attenuates the exhausted phenotype in vivo; single-cell RNA/TCR/ATAC-seq confirmed that Cxcr4-deficient CD8+ T cells epigenetically mitigate the transition from functional to exhausted phenotypes. CXCR4 blockade in vivo, Cxcr4 gene deficiency, single-cell RNA-seq/TCR-seq/ATAC-seq, JAK2/STAT3 pathway analysis Cell genomics High 39317187
2019 In gastric cancer, TOX expression is suppressed relative to normal tissue; sanguinarine increases TOX expression while decreasing DNA-PKcs and KU70/80 expression, inhibiting tumorigenesis via the TOX/DNA-PKcs/KU70/80 signaling pathway. Network pharmacology target identification, MTT/colony formation assays, xenograft tumor model, qRT-PCR and western blot for TOX/DNA-PKcs/KU70/80 Pathology, research and practice Low 31591052

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 1241 31207603
2019 TOX is a critical regulator of tumour-specific T cell differentiation. Nature 878 31207604
2019 TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 713 31207605
2019 TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proceedings of the National Academy of Sciences of the United States of America 613 31152140
2019 Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nature immunology 433 31209400
1990 The in vivo micronucleus assay in mammalian bone marrow and peripheral blood. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 382 2195332
1981 Sister-chromatid exchanges: a report of the GENE-TOX program. Mutation research 380 6173747
1981 Mutagenesis by chemical agents in V79 chinese hamster cells: a review and analysis of the literature. A report of the Gene-Tox Program. Mutation research 285 7035931
1983 An evaluation of the mouse sperm morphology test and other sperm tests in nonhuman mammals. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 283 6835246
1981 Mammalian in vivo and in vitro cytogenetic assays: a report of the U.S. EPA's gene-tox program. Mutation research 242 7035930
1986 The Salmonella typhimurium/mammalian microsomal assay. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 241 3528831
1990 Molecular cloning and DNA sequence analysis of a diphtheria tox iron-dependent regulatory element (dtxR) from Corynebacterium diphtheriae. Proceedings of the National Academy of Sciences of the United States of America 208 2116013
1982 Chromosome aberration assays in Allium. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 203 7177154
2019 VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers. Science immunology 189 31704735
2008 Development of all CD4 T lineages requires nuclear factor TOX. The Journal of experimental medicine 185 18195075
2020 TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells. Science immunology 181 32620560
1993 Sister-chromatid exchange: second report of the Gene-Tox Program. Mutation research 168 7687323
1994 Tagged mutations at the Tox1 locus of Cochliobolus heterostrophus by restriction enzyme-mediated integration. Proceedings of the National Academy of Sciences of the United States of America 160 7809094
2015 The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor. Nature immunology 153 25915732
2002 TOX: an HMG box protein implicated in the regulation of thymocyte selection. Nature immunology 151 11850626
2000 Biology and molecular epidemiology of diphtheria toxin and the tox gene. The Journal of infectious diseases 142 10657208
1983 The sex-linked recessive lethal test for mutagenesis in Drosophila melanogaster. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 133 6413857
1998 Structure of the metal-ion-activated diphtheria toxin repressor/tox operator complex. Nature 132 9697776
1983 An evaluation of human sperm as indicators of chemically induced alterations of spermatogenic function. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 131 6835247
1983 Unscheduled DNA synthesis tests. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 108 6358881
2018 A glass-based, continuously zonated and vascularized human liver acinus microphysiological system (vLAMPS) designed for experimental modeling of diseases and ADME/TOX. Lab on a chip 106 30063238
1984 Testing of chemicals for genetic activity with Saccharomyces cerevisiae: a report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 103 6374444
2023 Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure. Immunity 91 38091951
2011 The many roles of TOX in the immune system. Current opinion in immunology 91 22209117
1998 Multicenter evaluation of the Clostridium difficile TOX A/B TEST. Journal of clinical microbiology 87 9431944
2004 Tox-Prot, the toxin protein annotation program of the Swiss-Prot protein knowledgebase. Toxicon : official journal of the International Society on Toxinology 81 15683867
2004 Performance of the TechLab C. DIFF CHEK-60 enzyme immunoassay (EIA) in combination with the C. difficile Tox A/B II EIA kit, the Triage C. difficile panel immunoassay, and a cytotoxin assay for diagnosis of Clostridium difficile-associated diarrhea. Journal of clinical microbiology 78 15472364
2024 LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity. Cell 76 39121847
1985 Current status of bioassays in genetic toxicology--the dominant lethal assay. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 76 3889623
1987 Cloning, sequence determination, and expression in transfected cells of the coding sequence for the tox 176 attenuated diphtheria toxin A chain. Molecular and cellular biology 75 3110596
1992 Binding of the metalloregulatory protein DtxR to the diphtheria tox operator requires a divalent heavy metal ion and protects the palindromic sequence from DNase I digestion. The Journal of biological chemistry 69 1400485
1974 Synthesis of diphtheria tox-gene products in Escherichia coli extracts. Proceedings of the National Academy of Sciences of the United States of America 65 4204202
2020 TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection. Gut 64 33097558
2018 Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells. Immunity 63 29768177
2014 Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma. Blood 63 25548321
2020 TOX-expressing terminally exhausted tumor-infiltrating CD8+ T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer. Cancer letters 62 33249194
2004 TOX provides a link between calcineurin activation and CD8 lineage commitment. The Journal of experimental medicine 62 15078895
2019 3D-QSAR, Docking, ADME/Tox studies on Flavone analogs reveal anticancer activity through Tankyrase inhibition. Scientific reports 61 30932078
1992 Specific binding of the diphtheria tox regulatory element DtxR to the tox operator requires divalent heavy metal ions and a 9-base-pair interrupted palindromic sequence. Proceedings of the National Academy of Sciences of the United States of America 61 1631071
2011 TOX is required for development of the CD4 T cell lineage gene program. Journal of immunology (Baltimore, Md. : 1950) 59 22021617
1981 The GENE-TOX program: genetic activity evaluation. Journal of chemical information and computer sciences 57 7240352
2018 Organs-on-a-chip: Current applications and consideration points for in vitro ADME-Tox studies. Drug metabolism and pharmacokinetics 56 29398302
2020 Virtual screening, ADME/Tox predictions and the drug repurposing concept for future use of old drugs against the COVID-19. Life sciences 45 32535080
2014 ABC transporters in multi-drug resistance and ADME-Tox of small molecule tyrosine kinase inhibitors. Pharmaceutical research 45 24842659
1976 Characterization and genetic mapping of nontoxinogenic (tox) mutants of corynebacteriophage beta. Journal of virology 45 820871
1982 An evaluation of the host-mediated assay and body fluid analysis. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 44 7050697
2014 Emergence and molecular characterisation of non-toxigenic tox gene-bearing Corynebacterium diphtheriae biovar mitis in the United Kingdom, 2003-2012. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 42 24925458
2014 Tox: a multifunctional transcription factor and novel regulator of mammalian corticogenesis. The EMBO journal 42 25527292
2021 Increased lactate in AML blasts upregulates TOX expression, leading to exhaustion of CD8+ cytolytic T cells. American journal of cancer research 37 34873490
1976 Orientation of the tox gene in the prophage of corynebacteriophage beta. Journal of virology 37 820874
2021 Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8+ T cells. JCI insight 35 34032638
1988 The genetic toxicology of Gene-Tox non-carcinogens. Mutation research 35 3285185
2018 TRPs in Tox: Involvement of Transient Receptor Potential-Channels in Chemical-Induced Organ Toxicity-A Structured Review. Cells 34 30087301
2007 Biological fingerprinting analysis of traditional Chinese medicines with targeting ADME/Tox property for screening of bioactive compounds by chromatographic and MS methods. Mini reviews in medicinal chemistry 33 17266641
1988 A review and analysis of the Chinese hamster ovary/hypoxanthine guanine phosphoribosyl transferase assay to determine the mutagenicity of chemical agents. A report of phase III of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 32 3292898
1985 Characterization of the diphtheria tox transcript in Corynebacterium diphtheriae and Escherichia coli. Journal of bacteriology 31 2411714
1984 Mutation tests in Neurospora crassa. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 31 6231482
2021 Antigen-driven PD-1+ TOX+ BHLHE40+ and PD-1+ TOX+ EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ. European journal of immunology 30 33296081
2021 Increased frequency of TIGIT+CD73-CD8+ T cells with a TOX+ TCF-1low profile in patients with newly diagnosed and relapsed AML. Oncoimmunology 30 34211801
2019 MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation. Science advances 30 31844658
2005 Systems-ADME/Tox: resources and network approaches. Journal of pharmacological and toxicological methods 30 16054403
2022 CD4+ T cells in classical Hodgkin lymphoma express exhaustion associated transcription factors TOX and TOX2: Characterizing CD4+ T cells in Hodgkin lymphoma. Oncoimmunology 29 35111387
2021 Persistence of self-reactive CD8+ T cells in the CNS requires TOX-dependent chromatin remodeling. Nature communications 29 33579927
2016 TOX expression and role in CTCL. Journal of the European Academy of Dermatology and Venereology : JEADV 29 27345620
2024 CXCR4 orchestrates the TOX-programmed exhausted phenotype of CD8+ T cells via JAK2/STAT3 pathway. Cell genomics 27 39317187
2015 TOX gene: a novel target for human cancer gene therapy. American journal of cancer research 27 26885442
1982 DNA repair assays as tests for environmental mutagens. A report of the U.S. EPA Gene-Tox Program. Mutation research 27 7050696
2019 Dysregulation of the TOX-RUNX3 pathway in cutaneous T-cell lymphoma. Oncotarget 26 31139323
2019 LncRNA MALAT1 Suppression Protects Endothelium against oxLDL-Induced Inflammation via Inhibiting Expression of MiR-181b Target Gene TOX. Oxidative medicine and cellular longevity 26 31949884
2023 TOX regulates T lymphocytes differentiation and its function in tumor. Frontiers in immunology 24 36969216
2019 Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro. Molecules (Basel, Switzerland) 24 31817628
2025 Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate. Science immunology 23 40053604
2023 Cyclohexane-1,3-dione Derivatives as Future Therapeutic Agents for NSCLC: QSAR Modeling, In Silico ADME-Tox Properties, and Structure-Based Drug Designing Approach. ACS omega 23 36743017
2023 QSAR, ADME-Tox, molecular docking and molecular dynamics simulations of novel selective glycine transporter type 1 inhibitors with memory enhancing properties. Heliyon 23 36865465
2020 Expression pattern, regulation, and clinical significance of TOX in breast cancer. Cancer immunology, immunotherapy : CII 23 32757053
2019 Corynebacterium diphtheriae: Diphtheria Toxin, the tox Operon, and Its Regulation by Fe2+ Activation of apo-DtxR. Microbiology spectrum 23 31267892
1997 Analysis of heterogeneity of Corynebacterium diphtheriae toxin gene, tox, and its regulatory element, dtxR, by direct sequencing. Research in microbiology 23 9404504
2021 Hibiscus sabdariffa anthocyanins are potential modulators of estrogen receptor alpha activity with favourable toxicology: a computational analysis using molecular docking, ADME/Tox prediction, 2D/3D QSAR and molecular dynamics simulation. Journal of biomolecular structure & dynamics 22 34854367
2021 NLRP3 Regulates IL-4 Expression in TOX+ CD4+ T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression. Frontiers in immunology 20 34220814
2017 TOX and ADIPOQ Gene Polymorphisms Are Associated with Antipsychotic-Induced Weight Gain in Han Chinese. Scientific reports 20 28327672
2022 Increased TOX expression associates with exhausted T cells in patients with multiple myeloma. Experimental hematology & oncology 19 35246241
2015 Polymorphisms in TOX and NCOA2 genes and their associations with reproductive traits in cattle. Reproduction, fertility, and development 17 25482955
2009 Biochemical evidence for ToxR and ToxJ binding to the tox operons of Burkholderia glumae and mutational analysis of ToxR. Journal of bacteriology 17 19465657
2021 Increased TOX expression concurrent with PD-1, Tim-3, and CD244 in T cells from patients with non-Hodgkin lymphoma. Asia-Pacific journal of clinical oncology 16 33608984
2019 Chemical structure modifications and nano-technology applications for improving ADME-Tox properties, a review. Archiv der Pharmazie 16 30609117
2015 Differential expression of TOX by skin-infiltrating T cells in Sézary syndrome and erythrodermic dermatitis. Journal of cutaneous pathology 16 25777533
1982 Specific-locus mutation assays in Zea mays. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 16 7177157
2020 High-mobility group box (TOX) antibody a useful tool for the identification of B and T cell subpopulations. PloS one 15 32106280
2009 Spodoptera frugiperda X-tox protein, an immune related defensin rosary, has lost the function of ancestral defensins. PloS one 15 19710910
2015 TOX and CDKN2A/B Gene Polymorphisms Are Associated with Type 2 Diabetes in Han Chinese. Scientific reports 14 26139146
2023 Molecular modeling study of pyrrolidine derivatives as novel myeloid cell leukemia-1 inhibitors through combined 3D-QSAR, molecular docking, ADME/Tox and MD simulation techniques. Journal of biomolecular structure & dynamics 13 36841617
2020 Potential Therapeutic Approaches to Alzheimer's Disease By Bioinformatics, Cheminformatics And Predicted Adme-Tox Tools. Current neuropharmacology 13 31885353
2023 Fluorescence-based methods for studying activity and drug-drug interactions of hepatic solute carrier and ATP binding cassette proteins involved in ADME-Tox. Biochemical pharmacology 12 36758706
2022 The TOX subfamily: all-round players in the immune system. Clinical and experimental immunology 12 35485425
2019 Sanguinarine inhibits the tumorigenesis of gastric cancer by regulating the TOX/DNA-PKcs/ KU70/80 pathway. Pathology, research and practice 12 31591052