TBX21

Summary

TBX21 (T-box transcription factor 21, HGNC:11599) is a protein-coding gene on chromosome 17q21.32, encoding T-box transcription factor TBX21 (Q9UL17). Lineage-defining transcription factor which initiates Th1 lineage development from naive Th precursor cells both by activating Th1 genetic programs and by repressing the opposing Th2 and Th17 genetic programs.

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human ortholog of mouse Tbx21/Tbet gene. Studies in mouse show that Tbx21 protein is a Th1 cell-specific transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (IFNG). Expression of the human ortholog also correlates with IFNG expression in Th1 and natural killer cells, suggesting a role for this gene in initiating Th1 lineage development from naive Th precursor cells.

Source: NCBI Gene 30009 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 88 (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 19
• Clinical variants (ClinVar): 54 total — 1 pathogenic
• Phenotypes (HPO): 8
• Transcription factor: yes — 58 downstream targets (CollecTRI)
• MANE Select transcript: NM_013351

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11599
Approved symbol	TBX21
Name	T-box transcription factor 21
Location	17q21.32
Locus type	gene with protein product
Status	Approved
Aliases	TBLYM, T-bet
Ensembl gene	ENSG00000073861
Ensembl biotype	protein_coding
OMIM	604895
Entrez	30009

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000177694, ENST00000581328, ENST00000906368

RefSeq mRNA: 1 — MANE Select: NM_013351 NM_013351

CCDS: CCDS11514

Canonical transcript exons

ENST00000177694 — 6 exons

Exon	Start	End
ENSE00000735498	47744195	47744353
ENSE00000735501	47743071	47743192
ENSE00000735504	47742610	47742764
ENSE00000812587	47733236	47733945
ENSE00001043177	47744748	47746122
ENSE00001725880	47744482	47744543

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 97.90.

FANTOM5 (CAGE): breadth broad, TPM avg 5.1777 / max 471.7198, expressed in 308 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161373	4.6329	291
161374	0.3611	116
161375	0.1838	72

Top tissues by expression

276 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.90	gold quality
blood	UBERON:0000178	85.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.21	gold quality
diaphragm	UBERON:0001103	79.04	gold quality
spleen	UBERON:0002106	78.55	gold quality
lymph node	UBERON:0000029	75.16	gold quality
hair follicle	UBERON:0002073	72.97	gold quality
bone marrow cell	CL:0002092	71.87	silver quality
bone marrow	UBERON:0002371	70.71	gold quality
mucosa of urinary bladder	UBERON:0001259	70.21	gold quality
pancreatic ductal cell	CL:0002079	69.19	silver quality
olfactory bulb	UBERON:0002264	68.37	gold quality
type B pancreatic cell	CL:0000169	68.22	gold quality
leukocyte	CL:0000738	68.07	gold quality
epithelial cell of pancreas	CL:0000083	66.99	gold quality
left ventricle myocardium	UBERON:0006566	66.86	gold quality
cardiac muscle of right atrium	UBERON:0003379	66.81	gold quality
thymus	UBERON:0002370	66.79	gold quality
tibialis anterior	UBERON:0001385	66.25	silver quality
ileal mucosa	UBERON:0000331	65.65	gold quality
upper lobe of left lung	UBERON:0008952	65.53	gold quality
mononuclear cell	CL:0000842	65.46	gold quality
cerebellar vermis	UBERON:0004720	65.31	gold quality
vermiform appendix	UBERON:0001154	64.68	gold quality
vena cava	UBERON:0004087	64.63	gold quality
monocyte	CL:0000576	64.58	gold quality
caecum	UBERON:0001153	64.46	gold quality
upper lobe of lung	UBERON:0008948	63.84	gold quality
mucosa of paranasal sinus	UBERON:0005030	63.72	gold quality
right lung	UBERON:0002167	63.68	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	46.12
E-ANND-3	yes	12.18

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

58 targets.

Target	Regulation
ABL1
B3GAT1
BTK
CCL11
CCL3	Activation
CCL3L1
CCL4	Activation
CCR4	Repression
CD74
CD79A
CD8A
CDKN1B
CHST4	Activation
CXCR3	Activation
DUSP16
EGR2
ELAVL2
EOMES
FUT7	Unknown
GATA3	Unknown
GPR132
HAND1
HAND2
HAVCR2
ICOS
IFNG	Activation
IL10	Unknown
IL13	Repression
IL15
IL17A	Activation

JASPAR motifs

Motif	Name	Family
MA0690.1	TBX21	TBrain-related factors
MA0690.2	TBX21	TBrain-related factors
MA0690.3	TBX21	TBrain-related factors
MA2629.1	GSC::TBX21	Paired-related HD factors::TBX1-related factors

JASPAR matrix evidence (PMIDs): PMID:16285859, PMID:20211142

Upstream regulators (CollecTRI, top): AHR, BCL6, EZH2, HAND1, HAND2, IKZF1, NFKB1, ONECUT2, PITX2, PRDM1, PTPN22, RBPJ, RELA, SMAD3, SP1, STAT1, STAT4, TBX21, TOX2, USF1, YY1

miRNA regulators (miRDB)

36 targeting TBX21, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-20B-3P	99.29	67.05	784
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-1183	98.75	67.10	1116
HSA-MIR-6792-3P	98.41	66.86	1359
HSA-MIR-4691-5P	98.41	66.77	1343
HSA-MIR-4733-3P	98.35	65.20	994
HSA-MIR-4639-3P	97.54	67.12	787
HSA-MIR-4797-3P	97.48	67.14	989
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-526B-5P	97.41	67.99	1074

Literature-anchored findings (GeneRIF, showing 40)

• distribution of T-BET/TBX21 expression in the haematopoietic compartment (PMID:12128215)
• Among twenty-three novel polymorphisms identified in the human TBX21 gene of Korean asthma patients, no significant associations of TBX21 variants with risk of asthma were observed. (PMID:12938094)
• VZV virus and mite antigens induce expression of this transcriptionn factor in cord blood mononuclear cells, differenetially affecting Th1 and Th2 cells. (PMID:12960249)
• T-bet expression in T(H)2 cells induced IL-2 production and decreased the secretion of IL-4. (PMID:15131585)
• Association seen between type 1 diabetes and polymorphisms in the T-bet gene; variation in T-bet transcriptional activity may play a role in the development of type 1 diabetes, possibly through the effect on IFN-gamma production in Th1 cells (PMID:15241679)
• genetic variation in TBX21 may alter asthma phenotypes in a treatment-specific fashion (PMID:15604153)
• Expressed in Hodgkin disesase Reed Sternberg cells. (PMID:15632006)
• Data indicate that T-bet can override repressive epigenetic modification through a T-box half-site and dissociation of the mSin3a corepressor from the promoter. (PMID:15684083)
• T-bet may play a role in Hodgkin’s lymphoma oncogenesis (PMID:15712176)
• first report demonstrating relationship between TBX21 single nucleotide polymorphisms and aspirin-induced asthma in Japanese (PMID:15806396)
• female steroid hormones use Stat-mediated pathways to modulate the expression of T-bet in epithelial cells (PMID:15860546)
• T-bet was clearly induced in the two B-cell precursor-leukemia cell lines. (PMID:15927679)
• These data suggest that T-bet variation contributes to airway responsiveness in asthma. (PMID:16179640)
• Data from a prospective twin study suggest that T helper type 2 (Th2) cell-associated diseases in humans might be due to genetic variations in Th1 cytokine regulation via T-bet. (PMID:16210653)
• A key transcription factor that links the long-term renewal of memory CD8+ T cells to their characteristic effector potency. (PMID:16273099)
• Increased IFN-gamma levels observed in aplastic anemia patients are the result of active transcription of the IFN-gamma gene by T-bet. (PMID:16434488)
• Increased T-bet expression does not only identify intracellular infections in lymphoid tissue associated with high IFN-gamma levels, but also implies that, under these conditions, it becomes induced in B cells, which apparently support the Th1 response. (PMID:16487356)
• Segmental allergen challenge in asthmatics leads to increased GATA-3, c-maf and T-bet expression in BAL cells but not in bronchial biopsies (PMID:16498264)
• Among mite-allergic patients T-bet expression was down-regulated, which had no relation to ECP concentration and allergic symptoms. (PMID:16874959)
• Imbalance of transcription factors T-bet and GATA-3 may be one of the key factors in immune dysregulation of recurrent aphthous ulcerations. (PMID:17074191)
• the GATA-3/T-bet transcription factor complex regulates the cell-lineage-specific expression of the lymphocyte homing receptors (PMID:17075044)
• A defect in Wiskott Aldrich CD4+ T cells is due to reduction in T-bet mRNA expression and in early nuclear recruitment of NFAT-1. (PMID:17082665)
• There is an association between expression of Th1/Th2 transcription factors and cytokines (T-bet, GATA-3, IFN-gamma, IL-4,IL-18) in systemic lupus erythematosus. (PMID:17117487)
• suppression of T-bet ameliorates EAE by limiting the differentiation of autoreactive Th1 cells, as well as inhibiting pathogenic Th17 cells via regulation of IL-23R. (PMID:17237380)
• T-bet gene might be involved in the development of NK/T-cell lymphoma. (PMID:17325860)
• Genetic variations the TBX21 promoter region contribute to susceptibility to HBV infection in the Chinese population. (PMID:17378728)
• In Dermatophagoides farinae-stimulated PBMCs from patients with asthma, expression of GATA-3 and T-bet and FOPX3 expression is decreased. (PMID:17445472)
• In patients with acute asthma, rosiglitazone could regulate the balance of IFN-gamma and IL-4 by affecting expression of T-bet mRNA and GATA-3. (PMID:17445473)
• IL-4 gene transcription is inhibited by T-bet via the suppression of its promoter activity, independently of IFN-gamma. T-bet facilitates Th1 differentiation through not only upregulation of IFN-gamma, but also downregulation of IL-4 gene transcription. (PMID:17541280)
• Immunohistochemical detection of T-bet in infiltrated bone marrow trephines represents an important adjunct for the diagnosis of hairy cell leukemia. (PMID:17667540)
• Sp1 is a positive transcriptional regulator of T-BET (PMID:17705132)
• An association between a specific TBX21 haplotype and allergic asthma in children is demonstrated for the first time. (PMID:17949803)
• T-bet expression was down-regulated in NALT of patients with allergic rhinitis. (PMID:17993020)
• The expression patterns of T-Bet and GATA-3 oppose progesteron receptor, suggesting antagonistic function and/or regulation between PR and T-Bet/GATA-3 (PMID:18212358)
• low-dose prolactin induced T-bet expression and high-dose prolactin tended to suppress it (PMID:18414429)
• IL-13 expression was downregulated by T-bet at the level of gene transcription, independently of the modulation of Th1/Th2 balance. T-bet is the potential key factor in the development of Th1/Th2-related diseases. (PMID:18504404)
• T-bet mRNA expression level was significantly higher in patients with postoperative infection after aggressive hepatobiliary pancreatic surgery. (PMID:18619618)
• evaluated the frequencies of five different single-nucleotide polymorphisms (SNPs) in the TBX21 gene in 159 HSV-2-infected individuals and compared them with those in 186 healthy HSV-2-seronegative controls (PMID:18753235)
• The Axl/Gas6 pathway contributes to normal human NK-cell development via an effect on the master regulatory transcription factor T-BET. (PMID:18840707)
• oral graft vs host disease results from type I IFN-driven immigration, proliferation, and differentiation of T-bet(+) type I T effectors (PMID:19168793)

Cross-species orthologs

18 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbx21	ENSDARG00000004473
danio_rerio	tbxta	ENSDARG00000101576
mus_musculus	Tbx21	ENSMUSG00000001444
rattus_norvegicus	Tbx21	ENSRNOG00000009427
drosophila_melanogaster	H15	FBGN0016660
drosophila_melanogaster	Doc1	FBGN0028789
drosophila_melanogaster	Doc3	FBGN0035954
drosophila_melanogaster	Doc2	FBGN0035956
drosophila_melanogaster	mid	FBGN0261963
drosophila_melanogaster	ocm	FBGN0266083
caenorhabditis_elegans		WBGENE00003106
caenorhabditis_elegans		WBGENE00004750
caenorhabditis_elegans		WBGENE00006545
caenorhabditis_elegans		WBGENE00006546
caenorhabditis_elegans		WBGENE00006556
caenorhabditis_elegans		WBGENE00006557
caenorhabditis_elegans		WBGENE00006559
caenorhabditis_elegans		WBGENE00044798

Paralogs (16): TBX5 (ENSG00000089225), TBX15 (ENSG00000092607), TBX18 (ENSG00000112837), TBX2 (ENSG00000121068), TBX4 (ENSG00000121075), TBX22 (ENSG00000122145), TBX3 (ENSG00000135111), TBR1 (ENSG00000136535), TBX19 (ENSG00000143178), TBX6 (ENSG00000149922), EOMES (ENSG00000163508), TBXT (ENSG00000164458), TBX20 (ENSG00000164532), TBX10 (ENSG00000167800), MGA (ENSG00000174197), TBX1 (ENSG00000184058)

Protein

Protein identifiers

T-box transcription factor TBX21 — Q9UL17 (reviewed: Q9UL17)

Alternative names: T-cell-specific T-box transcription factor T-bet, Transcription factor TBLYM

All UniProt accessions (1): Q9UL17

UniProt curated annotations — full annotation on UniProt →

Function. Lineage-defining transcription factor which initiates Th1 lineage development from naive Th precursor cells both by activating Th1 genetic programs and by repressing the opposing Th2 and Th17 genetic programs. Activates transcription of a set of genes important for Th1 cell function, including those encoding IFN-gamma and the chemokine receptor CXCR3. Induces permissive chromatin accessibilty and CpG methylation in IFNG. Activates IFNG and CXCR3 genes in part by recruiting chromatin remodeling complexes including KDM6B, a SMARCA4-containing SWI/SNF-complex, and an H3K4me2-methyltransferase complex to their promoters and all of these complexes serve to establish a more permissive chromatin state conducive with transcriptional activation. Can activate Th1 genes also via recruitment of Mediator complex and P-TEFb (composed of CDK9 and CCNT1/cyclin-T1) in the form of the super elongation complex (SEC) to super-enhancers and associated genes in activated Th1 cells. Inhibits the Th17 cell lineage commitment by blocking RUNX1-mediated transactivation of Th17 cell-specific transcriptinal regulator RORC. Inhibits the Th2 cell lineage commitment by suppressing the production of Th2 cytokines, such as IL-4, IL-5, and IL- 13, via repression of transcriptional regulators GATA3 and NFATC2. Protects Th1 cells from amplifying aberrant type-I IFN response in an IFN-gamma abundant microenvironment by acting as a repressor of type-I IFN transcription factors and type-I IFN-stimulated genes. Acts as a regulator of antiviral B-cell responses; controls chronic viral infection by promoting the antiviral antibody IgG2a isotype switching and via regulation of a broad antiviral gene expression program. Required for the correct development of natural killer (NK) and mucosal-associated invariant T (MAIT) cells.

Subunit / interactions. Interacts with RUNX1, RUNX3, ITK, ABL1, RELA, CDK9 and KDM6B. The phosphorylated form (at Thr-303) interacts with NFATC2. Interacts with SMARCA4 in a KDM6B-dependent manner. Interacts with CCTN1. Interacts with USP10. The phosphorylated form (at Tyr-530) interacts with GATA3.

Subcellular location. Nucleus.

Tissue specificity. T-cell specific.

Post-translational modifications. Phosphorylations at Ser-53, Tyr-77, Ser-225 and Ser-513 are regulated by mTORC1. Phosphorylation at Tyr-530 is essential for its interaction GATA3. Phosphorylation at Tyr-220, Tyr-266 and Tyr-305 enhances its transcriptional activator activity. Phosphorylation at Thr-303 is required for its interaction with NFATC2. Ubiquitinated at Lys-314, leading to its degradation by the proteasome. Ubiquitination is essential for controlling protein stability, binding to the T-box-binding element of the IFN-gamma promoter, and for interaction with NFATC2 through induction of phosphorylation at Thr-303. Deubiquitinated by USP10 leading to its stabilization.

Disease relevance. Asthma, with nasal polyps and aspirin intolerance (ANPAI) [MIM:208550] A condition consisting of asthma, aspirin sensitivity and nasal polyposis. Nasal polyposis is due to chronic inflammation of the paranasal sinus mucosa, leading to protrusion of edematous polyps into the nasal cavities. Disease susceptibility is associated with variants affecting the gene represented in this entry. Immunodeficiency 88 (IMD88) [MIM:619630] An autosomal recessive disorder characterized by the development of disseminated mycobacterial disease following vaccination with BCG. Clinical features included fever, lymphadenopathy, and cutaneous eruption. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_037483* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001699	TF_T-box	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR018186	TF_T-box_CS	Conserved_site
IPR036960	T-box_sf	Homologous_superfamily
IPR046360	T-box_DNA-bd	Domain

Pfam: PF00907

UniProt features (21 total): modified residue 10, sequence variant 3, region of interest 3, chain 1, DNA-binding region 1, cross-link 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UL17-F1	61.95	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 305 (essential for its interaction with runx1 and its ability to inhibit runx1 transcriptional activity and suppress th17 lineage development)

Post-translational modifications (11): 220, 225, 266, 303, 305, 513, 530, 314, 53, 77, 118

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9942503	Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)

MSigDB gene sets: 383 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_B_CELL_ACTIVATION, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_PRODUCTION_OF_MOLECULAR_MEDIATOR_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION

GO Biological Process (21): negative regulation of transcription by RNA polymerase II (GO:0000122), cell fate specification (GO:0001708), T-helper 1 cell lineage commitment (GO:0002296), regulation of transcription by RNA polymerase II (GO:0006357), response to virus (GO:0009615), negative regulation of interleukin-2 production (GO:0032703), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of T cell differentiation (GO:0045580), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of isotype switching to IgG isotypes (GO:0048304), lymphocyte migration (GO:0072676), negative regulation of T-helper 17 cell differentiation (GO:2000320), negative regulation of T-helper 17 cell lineage commitment (GO:2000329), negative regulation of T-helper 2 cell cytokine production (GO:2000552), positive regulation of T-helper 1 cell cytokine production (GO:2000556), regulation of DNA-templated transcription (GO:0006355), positive regulation of gene expression (GO:0010628), T cell differentiation (GO:0030217), regulation of immune response (GO:0050776)

GO Molecular Function (10): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Differentiation of T cells	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
DNA-templated transcription	3
regulation of gene expression	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
negative regulation of DNA-templated transcription	1
cell fate commitment	1
cellular developmental process	1
T-helper cell lineage commitment	1
T-helper 1 cell differentiation	1
response to other organism	1
negative regulation of cytokine production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
T cell differentiation	1
regulation of lymphocyte differentiation	1
regulation of T cell activation	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
positive regulation of isotype switching	1
isotype switching to IgG isotypes	1
regulation of isotype switching to IgG isotypes	1
mononuclear cell migration	1
negative regulation of immune effector process	1
negative regulation of T-helper cell differentiation	1
T-helper 17 cell differentiation	1
negative regulation of T-helper 17 type immune response	1
regulation of T-helper 17 cell differentiation	1
negative regulation of cell fate commitment	1
T-helper 17 cell lineage commitment	1
negative regulation of T-helper 17 cell differentiation	1
regulation of T-helper 17 cell lineage commitment	1
negative regulation of T cell cytokine production	1
negative regulation of type 2 immune response	1
T-helper 2 cell cytokine production	1

Protein interactions and networks

STRING

2688 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBX21	GATA3	P23771	957
TBX21	CD4	P01730	944
TBX21	IFNG	P01579	942
TBX21	IL17A	Q16552	938
TBX21	FOXP3	Q9BZS1	931
TBX21	KDM6B	O15054	923
TBX21	CD8A	P01732	918
TBX21	BCL6	P41182	909
TBX21	RORC	P51449	906
TBX21	RUNX3	Q13761	892
TBX21	HLX	Q14774	889
TBX21	IL4	P05112	885
TBX21	STAT4	Q14765	885
TBX21	IL15	P40933	882
TBX21	IL12RB2	Q99665	868

IntAct

20 interactions, top by confidence:

A	B	Type	Score
TBX21	GATA3	psi-mi:“MI:0914”(association)	0.580
TBX21	GATA3	psi-mi:“MI:0915”(physical association)	0.580
TBX21	SP1	psi-mi:“MI:0915”(physical association)	0.580
TBX21	SP1	psi-mi:“MI:0914”(association)	0.580
GATA3	TBX21	psi-mi:“MI:0915”(physical association)	0.580
TBX21	CREBBP	psi-mi:“MI:0915”(physical association)	0.520
CREBBP	TBX21	psi-mi:“MI:0915”(physical association)	0.520
TBX21	EP300	psi-mi:“MI:0915”(physical association)	0.500
EP300	TBX21	psi-mi:“MI:0915”(physical association)	0.500
HOXC11	TBX21	psi-mi:“MI:0915”(physical association)	0.370
TBX21	ZNF490	psi-mi:“MI:0915”(physical association)	0.370
EXOC5	TBX21	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (15): TBX21 (Affinity Capture-MS), TBX21 (Cross-Linking-MS (XL-MS)), CREBBP (Affinity Capture-Western), EP300 (Affinity Capture-Western), GATA3 (Affinity Capture-Western), SP1 (Affinity Capture-Western), TBX21 (Affinity Capture-Western), TBX21 (Affinity Capture-Western), TBX21 (Affinity Capture-Western), TBX21 (Affinity Capture-Western), TBX21 (Two-hybrid), ZNF490 (Two-hybrid), TBX21 (Two-hybrid), USP10 (Affinity Capture-Western), UBC (Affinity Capture-Western)

ESM2 similar proteins: A1YF56, A2AEV7, A6NCS4, A7Y7W2, D3ZJK7, E1BEA8, F1MUS9, O15534, O35973, O43435, O43638, O60248, O75333, O77728, O94983, O95935, O95947, P22736, P46099, P51666, P56261, P57082, P70325, P70327, Q03484, Q0V8F0, Q15744, Q497V6, Q5DTT2, Q61660, Q61663, Q63HR2, Q64731, Q66JL1, Q6PZD9, Q6ZQN5, Q80Y50, Q810F8, Q861Q9, Q8AV66

Diamond homologs: A1YF56, A2AWL7, D3ZJK7, E1BEA8, O01409, O13161, O15119, O15178, O17212, O43435, O54839, O60806, O70306, O73718, O75333, O95935, O95936, O95947, P20293, P24781, P55965, P56158, P57082, P70323, P70324, P70325, P70326, P70327, P79742, P79777, P79778, P79779, P79944, P80492, P87377, P90971, Q07998, Q13207, Q16650, Q17134

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
STAT1	up-regulates	TBX21
TBX21	up-regulates	TBX21
TBX21	down-regulates	GATA3
GATA3	down-regulates	TBX21
TBX21	down-regulates	IL4	“transcriptional regulation”
TOX2	“up-regulates quantity by expression”	TBX21	“transcriptional regulation”
TBX21	“down-regulates quantity by repression”	IL10	“transcriptional regulation”
TBX21	“down-regulates quantity by repression”	IL2	“transcriptional regulation”
TBX21	“up-regulates quantity by expression”	IFNG	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

54 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	42
Likely benign	7
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1326844	NM_013351.2(TBX21):c.466_471delinsAGTTTA (p.Glu156_Met157delinsSerLeu)	Pathogenic

SpliceAI

962 predictions. Top by Δscore:

Variant	Effect	Δscore
17:47742604:CTCCA:C	acceptor_loss	1.0000
17:47742605:TCCAG:T	acceptor_loss	1.0000
17:47742606:CCAGG:C	acceptor_loss	1.0000
17:47742607:CA:C	acceptor_loss	1.0000
17:47742608:A:AG	acceptor_gain	1.0000
17:47742608:A:T	acceptor_loss	1.0000
17:47742608:AGGC:A	acceptor_gain	1.0000
17:47742608:AGGCG:A	acceptor_gain	1.0000
17:47742609:G:GT	acceptor_gain	1.0000
17:47742609:GGC:G	acceptor_gain	1.0000
17:47742609:GGCG:G	acceptor_gain	1.0000
17:47742609:GGCGG:G	acceptor_gain	1.0000
17:47742724:C:T	donor_gain	1.0000
17:47742727:G:GG	donor_gain	1.0000
17:47742762:CAGG:C	donor_loss	1.0000
17:47742763:AG:A	donor_loss	1.0000
17:47742764:GG:G	donor_loss	1.0000
17:47742765:G:T	donor_loss	1.0000
17:47742766:T:A	donor_loss	1.0000
17:47744186:T:TA	acceptor_gain	1.0000
17:47744192:C:G	acceptor_gain	1.0000
17:47744192:CA:C	acceptor_loss	1.0000
17:47744193:A:AG	acceptor_gain	1.0000
17:47744193:AGAT:A	acceptor_gain	1.0000
17:47744194:G:GA	acceptor_gain	1.0000
17:47744194:GA:G	acceptor_gain	1.0000
17:47744194:GAT:G	acceptor_gain	1.0000
17:47744194:GATG:G	acceptor_gain	1.0000
17:47744194:GATGA:G	acceptor_gain	1.0000
17:47744351:GAG:G	donor_gain	1.0000

AlphaMissense

3476 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:47733870:T:A	V139D	1.000
17:47733876:T:A	L141H	1.000
17:47733876:T:C	L141P	1.000
17:47733891:T:C	L146S	1.000
17:47733893:T:A	W147R	1.000
17:47733893:T:C	W147R	1.000
17:47733894:G:C	W147S	1.000
17:47733895:G:C	W147C	1.000
17:47733895:G:T	W147C	1.000
17:47733902:T:A	F150I	1.000
17:47733902:T:C	F150L	1.000
17:47733902:T:G	F150V	1.000
17:47733903:T:C	F150S	1.000
17:47733903:T:G	F150C	1.000
17:47733904:T:A	F150L	1.000
17:47733904:T:G	F150L	1.000
17:47733918:C:T	T155I	1.000
17:47733920:G:A	E156K	1.000
17:47733921:A:C	E156A	1.000
17:47733921:A:G	E156G	1.000
17:47733921:A:T	E156V	1.000
17:47733922:G:C	E156D	1.000
17:47733922:G:T	E156D	1.000
17:47733924:T:A	M157K	1.000
17:47733924:T:C	M157T	1.000
17:47733924:T:G	M157R	1.000
17:47733925:G:A	M157I	1.000
17:47733925:G:C	M157I	1.000
17:47733925:G:T	M157I	1.000
17:47733926:A:T	I158F	1.000

dbSNP variants (sampled 300 via entrez): RS1000631219 (17:47746614 G>A,C), RS1001075810 (17:47746326 C>T), RS1001193365 (17:47745907 T>G), RS1001312189 (17:47735783 A>C), RS1001331350 (17:47733292 A>AG), RS1001440754 (17:47735234 C>T), RS1001468647 (17:47733539 G>A,C,T), RS1001810114 (17:47735457 T>A), RS1002198791 (17:47741452 C>A), RS1002374085 (17:47745642 G>A), RS1002588744 (17:47735043 C>G,T), RS1003086686 (17:47744577 C>T), RS1003405974 (17:47746281 C>T), RS1003538012 (17:47744660 G>A), RS1003676075 (17:47731813 T>C)

Disease associations

OMIM: gene MIM:604895 | disease phenotypes: MIM:619630, MIM:208550

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 88	Limited	Autosomal recessive
asthma, nasal polyps, and aspirin intolerance	Limited	Autosomal recessive

Mondo (2): immunodeficiency 88 (MONDO:0030483), asthma, nasal polyps, and aspirin intolerance (MONDO:0008834)

Orphanet (0):

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001880	Increased total eosinophil count
HP:0002099	Asthma
HP:0003593	Infantile onset
HP:0012042	Aspirin-induced asthma
HP:0020087	BCGosis
HP:0100582	Nasal polyposis
HP:4000007	Bronchoconstriction

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST001341_8	Multiple sclerosis	1.000000e-07
GCST004557_34	Body mass index	2.000000e-08
GCST004558_1	Body mass index (joint analysis main effects and physical activity interaction)	3.000000e-09
GCST004560_22	Body mass index in physically inactive individuals	3.000000e-06
GCST004602_295	Mean corpuscular volume	2.000000e-11
GCST004630_217	Mean corpuscular hemoglobin	4.000000e-10
GCST005529_24	Ankylosing spondylitis	2.000000e-12
GCST005529_42	Ankylosing spondylitis	6.000000e-15
GCST005951_16	Body mass index	4.000000e-08
GCST005951_17	Body mass index	3.000000e-09
GCST006479_150	Diverticular disease	7.000000e-08
GCST007798_103	Asthma	1.000000e-09
GCST007995_4	Asthma (childhood onset)	3.000000e-09
GCST008551_1	Simvastatin-induced myopathy	4.000000e-06
GCST008916_117	Asthma	1.000000e-09
GCST010571_69	Autoimmune thyroid disease	3.000000e-15
GCST010703_72	Brain morphology (MOSTest)	3.000000e-08
GCST90014325_66	Asthma	5.000000e-10
GCST90020028_1415	Hip circumference adjusted for BMI	6.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008002	physical activity measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0009959	diverticular disease
EFO:0004346	neuroimaging measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2240017	Efficacy	3	corticosteroids	Asthma

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2240017	TBX21	3	2.50	1	corticosteroids
rs17244587	TBX21		0.00	0
rs17250932	TBX21		0.00	0

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
2-(1’H-indole-3’-carbonyl)thiazole-4-carboxylic acid methyl ester	affects expression, affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	affects methylation	2
CBP30 compound	decreases expression	1
TL8-506	increases expression, affects cotreatment	1
triphenyl phosphate	affects expression	1
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
tebuconazole	increases expression	1
6-formylindolo(3,2-b)carbazole	affects expression	1
abrine	increases expression	1
Acetaminophen	decreases expression	1
Aspirin	affects response to substance	1
Vehicle Emissions	decreases expression	1
Estradiol	increases reaction, increases expression, affects binding, decreases reaction	1
Formaldehyde	decreases expression	1
Latex	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Nickel	increases expression	1
Perfume	increases expression	1
Silicon Dioxide	increases expression	1
Tamoxifen	decreases response to substance	1
Tetrachlorodibenzodioxin	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Dinoprostone	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8QI	Abcam HCT 116 TBX21 KO	Cancer cell line	Male
CVCL_B9SZ	Abcam A-549 TBX21 KO	Cancer cell line	Male
CVCL_TR76	HAP1 TBX21 (-) 1	Cancer cell line	Male
CVCL_XU09	HAP1 TBX21 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

2 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01681615	Not specified	UNKNOWN	Challenge Test for Acetylsalicylic Acid Hypersensitivity
NCT02064738	Not specified	COMPLETED	High Omega-3/Low Omega-6 Treatment Diet for Aspirin-exacerbated Respiratory Disease (AERD)