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Gene Review

TBX21  -  T-box 21

Homo sapiens

Synonyms: T-PET, T-bet, T-box protein 21, T-box transcription factor TBX21, T-cell-specific T-box transcription factor T-bet, ...
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Disease relevance of TBX21

  • T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17 [1].
  • In addition, under these conditions, Th1 cells from T-bet-/- mice manifest IFNG promotor accessibility as detected by histone acetylation and deoxyribonuclease I hypersensitivity [2].
  • Here we report that mice lacking T-bet, a T-box transcription factor required for T helper (Th)1 cell differentiation and interferon (IFN)-gamma production, develop severe autoimmune heart disease compared to T-bet+/+ control mice [1].
  • Expression of the T-cell transcription factors, GATA-3 and T-bet, in the neoplastic cells of Hodgkin lymphomas [3].
  • OBJECTIVE: We sought to investigate the effects of ectopic T-bet expression in highly polarized human T(H)2 cells obtained from skin biopsy specimens of patients with atopic dermatitis [4].

Psychiatry related information on TBX21


High impact information on TBX21

  • GATA-3 for Th2 and T-bet for Th1 cells expressing interleukin-4 or interferon-gamma, respectively, are prime candidates for key transcription factors of cytokine memory [6].
  • CNS-22 was uniquely associated with histone modifications typical of accessible chromatin in both T helper 1 (Th1) and Th2 cells and demonstrated significant and selective T-bet (T-box transcription factor expressed in T cells, Tbx21)-dependent binding and enhancer activity in Th1 cells [7].
  • T-bet induction in A. fumigatus-specific CD4(+) T cells was enhanced by MyD88-mediated signals in draining lymph nodes, but T cell proliferation, trafficking, and Th1 differentiation in the airways were Toll-like receptor (TLR) and MyD88 independent [8].
  • Our data indicate that cytokine gene expression in T(H)1 cells may be controlled by a feed-forward regulatory circuit in which T-bet induces Runx3 and then 'partners' with Runx3 to direct lineage-specific gene activation and silencing [9].
  • The observation that the T-bet transcription factor allows tissue-specific upregulation of intracellular osteopontin (Opn-i) in plasmacytoid dendritic cells (pDCs) suggests that Opn might contribute to the expression of interferon-alpha (IFN-alpha) in those cells [10].

Biological context of TBX21

  • Because airway responsiveness is moderated by the use of inhaled corticosteroids in asthma, it is conceivable that genetic variation in TBX21 may alter asthma phenotypes in a treatment-specific fashion [11].
  • Furthermore, our data indicate that the -1993T-->C substitution increases the affinity of a particular nuclear protein to the binding site of TBX21 covering the -1993 position, resulting in increased transcriptional activity of the TBX21 gene [12].
  • In order to examine whether polymorphisms in the candidate gene, TBX21, located on chromosome 17q21.32, are related to the risk of human asthma phenotypes, we have searched for genetic variations in the human TBX21 gene and identified 24 single nucleotide polymorphisms (SNPs), including five novel SNPs, by direct sequencing in Japanese subjects [12].
  • Association analysis of novel TBX21 variants with asthma phenotypes [13].
  • As a potent candidate gene for asthma genetic study, we have sequenced the full gene of human TBX21, including the -1,500bp promoter region to identify its gene polymorphisms [13].

Anatomical context of TBX21


Associations of TBX21 with chemical compounds


Physical interactions of TBX21

  • These results indicate that the GATA-3/T-bet transcription factor complex regulates the cell-lineage-specific expression of the lymphocyte homing receptors [21].
  • Patients' T-bet bound directly to the proximal site of the IFN-gamma promoter without any prior stimulation, in contrast to healthy controls [23].

Regulatory relationships of TBX21

  • Human TBX21 expressed in T Cells (T-BOX21) is a Th1-specific T-box transcription factor that controls the expression of the hallmark Th1 cytokine, IFNG [13].
  • However, VZV did not up-regulate T-bet or down-regulate GATA-3 expression significantly in CBMC [24].
  • Furthermore, sustained T-bet expression in human T(H)2 cells induced IL-2 production and decreased the secretion of IL-4 [4].
  • We now report that IL-12, a signature of cell-mediated immunity, represses Eomes while positively regulating T-bet in effector CD8(+) T cells during infection with Listeria monocytogenes [25].
  • Moreover, T-bet was found to directly regulate transcription of the IL-23R, and, in doing so, influenced the fate of Th17 cells, which depend on optimal IL-23 production for survival [26].

Other interactions of TBX21

  • In ex vivo organ cultures of H. pylori-infected biopsies, neutralization of endogenous IL-12 down-regulated the expression of phosphorylated STAT4 and T-bet and reduced IFN-gamma production [27].
  • In addition, H. pylori-infected biopsies exhibited high levels of expression of phosphorylated STAT4 and T-bet [27].
  • The levels of signal transducer and activator of transcription 4 (STAT4), STAT6, and T-box expressed in T cells (T-bet) in total proteins extracted from gastric biopsies were determined by Western blotting [27].
  • In conclusion, the level of T-bet expression is correlated with Th1/Th2 polarization status, whereas GATA-3 is a crucial factor in determining the IL-3 and IL-13 producing capacity of human T cells [28].
  • Furthermore, we have examined the levels of GATA3, c-Maf, T-bet, and Ets-related molecule during human Th1/Th2 differentiation and suggest that differences in the levels of these critical transcription factors are responsible for commitment toward the Th1 or Th2 lineage [29].

Analytical, diagnostic and therapeutic context of TBX21

  • Immunohistochemistry in HL tissues revealed that in 11 of 12 (92%) of the classical HL cases HRS cells were GATA-3 and/or T-bet positive [3].
  • METHODS: The cytokine production of T(H)2 cells retrovirally transfected with a vector expressing human T-bet was determined by means of intracellular FACS staining and ELISA [4].
  • The effects of T-bet transfection were analyzed at the mRNA level by means of real-time PCR and DNA microarrays and confirmed by using functional chemokine response assays [4].
  • A Hodgkin's lymphoma-derived cell line, L1236, expresses T-bet by Western blot analysis as well as by immunohistochemical staining [30].
  • Real-time semiquantitative PCR analysis of peripheral blood mononuclear cells in the peripheral blood showed a transient decrease of T-bet mRNA [31].


  1. T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17. Rangachari, M., Mauermann, N., Marty, R.R., Dirnhofer, S., Kurrer, M.O., Komnenovic, V., Penninger, J.M., Eriksson, U. J. Exp. Med. (2006) [Pubmed]
  2. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. Usui, T., Preiss, J.C., Kanno, Y., Yao, Z.J., Bream, J.H., O'Shea, J.J., Strober, W. J. Exp. Med. (2006) [Pubmed]
  3. Expression of the T-cell transcription factors, GATA-3 and T-bet, in the neoplastic cells of Hodgkin lymphomas. Atayar, C., Poppema, S., Blokzijl, T., Harms, G., Boot, M., van den Berg, A. Am. J. Pathol. (2005) [Pubmed]
  4. Sustained T-bet expression confers polarized human TH2 cells with TH1-like cytokine production and migratory capacities. Lametschwandtner, G., Biedermann, T., Schwärzler, C., Günther, C., Kund, J., Fassl, S., Hinteregger, S., Carballido-Perrig, N., Szabo, S.J., Glimcher, L.H., Carballido, J.M. J. Allergy Clin. Immunol. (2004) [Pubmed]
  5. Combining cytokine signalling with T-bet and GATA-3 regulation in Th1 and Th2 differentiation: a model for cellular decision-making. Yates, A., Callard, R., Stark, J. J. Theor. Biol. (2004) [Pubmed]
  6. Cytokine memory of T helper lymphocytes. Löhning, M., Richter, A., Radbruch, A. Adv. Immunol. (2002) [Pubmed]
  7. A distal conserved sequence element controls ifng gene expression by T cells and NK cells. Hatton, R.D., Harrington, L.E., Luther, R.J., Wakefield, T., Janowski, K.M., Oliver, J.R., Lallone, R.L., Murphy, K.M., Weaver, C.T. Immunity (2006) [Pubmed]
  8. Innate Immune Activation and CD4(+) T Cell Priming during Respiratory Fungal Infection. Rivera, A., Ro, G., Van Epps, H.L., Simpson, T., Leiner, I., Sant'angelo, D.B., Pamer, E.G. Immunity (2006) [Pubmed]
  9. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Djuretic, I.M., Levanon, D., Negreanu, V., Groner, Y., Rao, A., Ansel, K.M. Nat. Immunol. (2007) [Pubmed]
  10. Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Shinohara, M.L., Lu, L., Bu, J., Werneck, M.B., Kobayashi, K.S., Glimcher, L.H., Cantor, H. Nat. Immunol. (2006) [Pubmed]
  11. TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids. Tantisira, K.G., Hwang, E.S., Raby, B.A., Silverman, E.S., Lake, S.L., Richter, B.G., Peng, S.L., Drazen, J.M., Glimcher, L.H., Weiss, S.T. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  12. Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Akahoshi, M., Obara, K., Hirota, T., Matsuda, A., Hasegawa, K., Takahashi, N., Shimizu, M., Nakashima, K., Cheng, L., Doi, S., Fujiwara, H., Miyatake, A., Fujita, K., Higashi, N., Taniguchi, M., Enomoto, T., Mao, X.Q., Nakashima, H., Adra, C.N., Nakamura, Y., Tamari, M., Shirakawa, T. Hum. Genet. (2005) [Pubmed]
  13. Association analysis of novel TBX21 variants with asthma phenotypes. Chung, H.T., Kim, L.H., Park, B.L., Lee, J.H., Park, H.S., Choi, B.W., Hong, S.J., Chae, S.C., Kim, J.J., Park, C.S., Shin, H.D. Hum. Mutat. (2003) [Pubmed]
  14. Developmental expression of the T-box transcription factor T-bet/Tbx21 during mouse embryogenesis. Faedo, A., Ficara, F., Ghiani, M., Aiuti, A., Rubenstein, J.L., Bulfone, A. Mech. Dev. (2002) [Pubmed]
  15. Cloning and characterization of a new member of the T-box gene family. Zhang, W.X., Yang, S.Y. Genomics (2000) [Pubmed]
  16. Identification of a novel type 1 diabetes susceptibility gene, T-bet. Sasaki, Y., Ihara, K., Matsuura, N., Kohno, H., Nagafuchi, S., Kuromaru, R., Kusuhara, K., Takeya, R., Hoey, T., Sumimoto, H., Hara, T. Hum. Genet. (2004) [Pubmed]
  17. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Intlekofer, A.M., Takemoto, N., Wherry, E.J., Longworth, S.A., Northrup, J.T., Palanivel, V.R., Mullen, A.C., Gasink, C.R., Kaech, S.M., Miller, J.D., Gapin, L., Ryan, K., Russ, A.P., Lindsten, T., Orange, J.S., Goldrath, A.W., Ahmed, R., Reiner, S.L. Nat. Immunol. (2005) [Pubmed]
  18. T-bet antagonizes mSin3a recruitment and transactivates a fully methylated IFN-gamma promoter via a conserved T-box half-site. Tong, Y., Aune, T., Boothby, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  19. Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells. Arora, M., Chen, L., Paglia, M., Gallagher, I., Allen, J.E., Vyas, Y.M., Ray, A., Ray, P. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  20. IFN-{gamma} and T-bet Expression in Human Dendritic Cells from Normal Donors and Cancer Patients Is Controlled through Mechanisms Involving ERK-1/2-Dependent and IL-12-Independent Pathways. Li, H., Wojciechowski, W., Dell'agnola, C., Lopez, N.E., Espinoza-Delgado, I. J. Immunol. (2006) [Pubmed]
  21. Interaction of GATA-3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes. Chen, G.Y., Osada, H., Santamaria-Babi, L.F., Kannagi, R. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  22. Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: evidence of possible gene-gene interaction and alterations in Th1/Th2 cytokines. Gourh, P., Agarwal, S.K., Divecha, D., Assassi, S., Paz, G., Arora-Singh, R.K., Reveille, J.D., Shete, S., Mayes, M.D., Arnett, F.C., Tan, F.K. Arthritis Rheum. (2009) [Pubmed]
  23. T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia. Solomou, E.E., Keyvanfar, K., Young, N.S. Blood (2006) [Pubmed]
  24. Different antigens trigger different Th1/Th2 reactions in neonatal mononuclear cells (MNCs) relating to T-bet/GATA-3 expression. Yu, H.R., Chang, J.C., Chen, R.F., Chuang, H., Hong, K.C., Wang, L., Yang, K.D. J. Leukoc. Biol. (2003) [Pubmed]
  25. Cutting Edge: IL-12 Inversely Regulates T-bet and Eomesodermin Expression during Pathogen-Induced CD8+ T Cell Differentiation. Takemoto, N., Intlekofer, A.M., Northrup, J.T., Wherry, E.J., Reiner, S.L. J. Immunol. (2006) [Pubmed]
  26. T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity. Gocke, A.R., Cravens, P.D., Ben, L.H., Hussain, R.Z., Northrop, S.C., Racke, M.K., Lovett-Racke, A.E. J. Immunol. (2007) [Pubmed]
  27. Interleukin-12 Drives the Th1 Signaling Pathway in Helicobacter pylori-Infected Human Gastric Mucosa. Pellicanò, A., Sebkova, L., Monteleone, G., Guarnieri, G., Imeneo, M., Pallone, F., Luzza, F. Infect. Immun. (2007) [Pubmed]
  28. Correlation between mRNA expression of Th1/Th2 cytokines and their specific transcription factors in human helper T-cell clones. Kitamura, N., Kaminuma, O., Mori, A., Hashimoto, T., Kitamura, F., Miyagishi, M., Taira, K., Miyatake, S. Immunol. Cell Biol. (2005) [Pubmed]
  29. Cytokine coexpression during human Th1/Th2 cell differentiation: direct evidence for coordinated expression of Th2 cytokines. Cousins, D.J., Lee, T.H., Staynov, D.Z. J. Immunol. (2002) [Pubmed]
  30. T-bet, a T cell-associated transcription factor, is expressed in Hodgkin's lymphoma. Dorfman, D.M., Hwang, E.S., Shahsafaei, A., Glimcher, L.H. Hum. Pathol. (2005) [Pubmed]
  31. Intratumoral administration of recombinant human interleukin 12 in head and neck squamous cell carcinoma patients elicits a T-helper 1 profile in the locoregional lymph nodes. van Herpen, C.M., Looman, M., Zonneveld, M., Scharenborg, N., de Wilde, P.C., van de Locht, L., Merkx, M.A., Adema, G.J., de Mulder, P.H. Clin. Cancer Res. (2004) [Pubmed]
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