TISIDB

Summary
Symbol	TBX21
Name	T-box 21
Aliases	TBLYM; T-bet; T-PET; TBET; T-box expressed in T cells; T-box protein 21; T-cell-specific T-box transcription ......
Chromosomal Location	17q21.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Nucleus
Domain	PF00907 T-box
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 (PubMed:10761931). Activates transcription of a set of genes important for Th1 cell function, including those encoding IFN-gamma and the chemokine receptor CXCR3. 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 (By similarity). 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 (PubMed:27292648). 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 (By similarity).

> Gene Ontology [ TOP ]
Biological Process	GO:0000018 regulation of DNA recombination GO:0002200 somatic diversification of immune receptors GO:0002204 somatic recombination of immunoglobulin genes involved in immune response GO:0002208 somatic diversification of immunoglobulins involved in immune response GO:0002250 adaptive immune response GO:0002263 cell activation involved in immune response GO:0002285 lymphocyte activation involved in immune response GO:0002312 B cell activation involved in immune response GO:0002366 leukocyte activation involved in immune response GO:0002377 immunoglobulin production GO:0002381 immunoglobulin production involved in immunoglobulin mediated immune response GO:0002440 production of molecular mediator of immune response GO:0002443 leukocyte mediated immunity GO:0002449 lymphocyte mediated immunity GO:0002460 adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains GO:0002521 leukocyte differentiation GO:0002562 somatic diversification of immune receptors via germline recombination within a single locus GO:0002637 regulation of immunoglobulin production GO:0002639 positive regulation of immunoglobulin production GO:0002694 regulation of leukocyte activation GO:0002696 positive regulation of leukocyte activation GO:0002697 regulation of immune effector process GO:0002699 positive regulation of immune effector process GO:0002700 regulation of production of molecular mediator of immune response GO:0002702 positive regulation of production of molecular mediator of immune response GO:0002703 regulation of leukocyte mediated immunity GO:0002705 positive regulation of leukocyte mediated immunity GO:0002706 regulation of lymphocyte mediated immunity GO:0002708 positive regulation of lymphocyte mediated immunity GO:0002712 regulation of B cell mediated immunity GO:0002714 positive regulation of B cell mediated immunity GO:0002819 regulation of adaptive immune response GO:0002821 positive regulation of adaptive immune response GO:0002822 regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains GO:0002824 positive regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains GO:0002889 regulation of immunoglobulin mediated immune response GO:0002891 positive regulation of immunoglobulin mediated immune response GO:0006310 DNA recombination GO:0007159 leukocyte cell-cell adhesion GO:0009615 response to virus GO:0016064 immunoglobulin mediated immune response GO:0016444 somatic cell DNA recombination GO:0016445 somatic diversification of immunoglobulins GO:0016447 somatic recombination of immunoglobulin gene segments GO:0019724 B cell mediated immunity GO:0030098 lymphocyte differentiation GO:0030217 T cell differentiation GO:0042110 T cell activation GO:0042113 B cell activation GO:0045190 isotype switching GO:0045191 regulation of isotype switching GO:0045830 positive regulation of isotype switching GO:0045911 positive regulation of DNA recombination GO:0048291 isotype switching to IgG isotypes GO:0048302 regulation of isotype switching to IgG isotypes GO:0048304 positive regulation of isotype switching to IgG isotypes GO:0050864 regulation of B cell activation GO:0050865 regulation of cell activation GO:0050867 positive regulation of cell activation GO:0050871 positive regulation of B cell activation GO:0050900 leukocyte migration GO:0051052 regulation of DNA metabolic process GO:0051054 positive regulation of DNA metabolic process GO:0051249 regulation of lymphocyte activation GO:0051251 positive regulation of lymphocyte activation GO:0070486 leukocyte aggregation GO:0070489 T cell aggregation GO:0071593 lymphocyte aggregation GO:0072676 lymphocyte migration
Molecular Function	-
Cellular Component	GO:0043025 neuronal cell body GO:0044297 cell body

> KEGG and Reactome Pathway [ TOP ]
KEGG	-
Reactome	-

Summary
Symbol	TBX21
Name	T-box 21
Aliases	TBLYM; T-bet; T-PET; TBET; T-box expressed in T cells; T-box protein 21; T-cell-specific T-box transcription ......
Chromosomal Location	17q21.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between TBX21 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between TBX21 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26404003	Lung Cacinoma	Promote immunity (infiltration)	Systemic DLL-1 administration increased T-cell infiltration into tumors and elevated numbers of CD44(+)CD62L(+)CD8(+) memory T cells while decreasing the number of regulatory T cells and limiting tumor vascularization. This treatment was associated with upregulation of Notch and its ligands in tumor-infiltrating T cells enhanced expression of T-bet and phosphorylation of Stat1/2.
25480946	Head and Neck Squamous Cell Carcinoma	Promote immunity (T cell function)	SHP-2 activation by fusaruside suppresses p-STAT1/T-bet and production of Th1 cytokines. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T-cell activation and thereby reverse immunosuppression in the tumor microenvironment.
27775550	Acute myeloid leukemia	Promote immunity	Indeed, NK cells from leukemic mice and humans with AML showed lower levels of TBET and EOMES, transcription factors that are critical for terminal NK cell differentiation.
19688743	Melanoma	Promote immunity (T cell function)	Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site. Activation of p38 MAP kinase, but not ERK or JNK, by either TCR-stimuli or IL-12 and IL-18 is diminished in Gadd45b(-/-) CD8(+) T cells, resulting in reduced production of IFN-gamma. In addition, mRNA of T-bet and Eomes were reduced in Gadd45b(-/-) CD8(+) T cells, supporting a critical role of Gadd45b in shaping the Th1 fate.
20713880	Melanoma	Promote immunity (infiltration)	In this paper, we show that the combined germline deletion of T-bet and T cell-specific deletion of Eomes resulted in profound defects in adaptive antitumor immune responses. T-bet and Eomes drive Tc1 differentiation by preventing alternative CD8(+) T cell differentiation to Tc17 or Tc2 cells. Surprisingly, T-bet and Eomes are not critical for the generation of systemic CTL activities against cancer cells. Instead, T-bet and Eomes are crucial for tumor infiltration by CD8(+) T cells.
24415778	Colorectal Carcinoma	Promote immunity	We found that mice deficient for the T-box transcription factor T-bet lack terminally differentiated antitumor CD27(low)KLRG1(+) NK cells, leading to a terminal course of rapid-onset pulmonary CRC metastases.
22215017	Sarcoma	Promote immunity (infiltration)	We have recently shown that intratumor (i.t.) injection of syngenic dendritic cells (DC) engineered to express the transcription factor Tbet (TBX21) promotes protective type-1 T cell-mediated immunity via a mechanism that is largely interleukin (IL)-12p70-independent. Mice bearing established subcutaneous (s.c.) tumors injected with DC concomitantly expressing ectopic Tbet and IL12 (i.e., DC.Tbet/IL12) displayed superior (i) rates of tumor rejection and extended overall survival, (ii) cross-priming of Tc1 reactive against antigens expressed within the tumor microenvironment, and (iii) infiltration of CD8(+) T cells into treated tumors in association with elevated locoregional production of CXCR3 ligand chemokines.

Summary
Symbol	TBX21
Name	T-box 21
Aliases	TBLYM; T-bet; T-PET; TBET; T-box expressed in T cells; T-box protein 21; T-cell-specific T-box transcription ......
Chromosomal Location	17q21.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of TBX21 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	TBX21
Name	T-box 21
Aliases	TBLYM; T-bet; T-PET; TBET; T-box expressed in T cells; T-box protein 21; T-cell-specific T-box transcription ......
Chromosomal Location	17q21.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of TBX21 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	-0.142	0.693
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.282	0.643
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.454	0.381
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.108	0.873
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.547	0.656
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.931	0.538
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.852	0.129
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.982	0.235
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.644	0.465
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	1.039	0.0867
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	1.129	0.162
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.204	0.38

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of TBX21 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	1.4	2.3	0.469
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	1.7	2	0.532
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	11.8	-11.8	0.193
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	18.2	-18.2	0.199
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	6.2	-6.2	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	11.1	-11.1	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	5.3	0	5.3	0.507
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	12.5	0	12.5	0.485
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	TBX21
Name	T-box 21
Aliases	TBLYM; T-bet; T-PET; TBET; T-box expressed in T cells; T-box protein 21; T-cell-specific T-box transcription ......
Chromosomal Location	17q21.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of TBX21. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	TBX21
Name	T-box 21
Aliases	TBLYM; T-bet; T-PET; TBET; T-box expressed in T cells; T-box protein 21; T-cell-specific T-box transcription ......
Chromosomal Location	17q21.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of TBX21. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by TBX21. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	TBX21
Name	T-box 21
Aliases	TBLYM; T-bet; T-PET; TBET; T-box expressed in T cells; T-box protein 21; T-cell-specific T-box transcription ......
Chromosomal Location	17q21.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of TBX21. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	TBX21
Name	T-box 21
Aliases	TBLYM; T-bet; T-PET; TBET; T-box expressed in T cells; T-box protein 21; T-cell-specific T-box transcription ......
Chromosomal Location	17q21.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of TBX21 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	TBX21
Name	T-box 21
Aliases	TBLYM; T-bet; T-PET; TBET; T-box expressed in T cells; T-box protein 21; T-cell-specific T-box transcription ......
Chromosomal Location	17q21.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between TBX21 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	TBX21
Name	T-box 21
Aliases	TBLYM; T-bet; T-PET; TBET; T-box expressed in T cells; T-box protein 21; T-cell-specific T-box transcription ......
Chromosomal Location	17q21.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting TBX21 collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

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