TBX21

T-box transcription factor TBX21, also called T-bet (T-box expressed in T cells), is a protein that in humans is encoded by the TBX21 gene. Though being for long thought of only as a master regulator of type 1 immune response, T-bet has recently been shown to be implicated in development of various immune cell subsets and maintenance of mucosal homeostasis.

TBX21
Identifiers
Aliases	TBX21, T-PET, T-bet, TBET, TBLYM, T-box 21, T-box transcription factor 21, IMD88
External IDs	OMIM: 604895; MGI: 1888984; HomoloGene: 8353; GeneCards: TBX21; OMA:TBX21 - orthologs
Gene location (Human) Chr. Chromosome 17 (human) Band 17q21.32 Start 47,733,236 bp End 47,746,122 bp
Gene location (Mouse) Chr. Chromosome 11 (mouse) Band 11|11 D Start 96,988,897 bp End 97,006,157 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte blood testicle spleen lymph node bone marrow cells tibialis anterior muscle mucosa of ileum upper lobe of left lung mononuclear cell Top expressed in female urethra blood olfactory bulb embryo spleen mesenteric lymph nodes spinal ganglia extraocular muscle thymus granulocyte More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA-binding transcription factor activity DNA binding DNA-binding transcription repressor activity, RNA polymerase II-specific sequence-specific DNA binding protein binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component soma nucleus Biological process multicellular organism development positive regulation of transcription, DNA-templated cellular response to organic substance positive regulation of isotype switching to IgG isotypes response to virus T cell differentiation regulation of transcription, DNA-templated lymphocyte migration transcription, DNA-templated regulation of immune response negative regulation of transcription by RNA polymerase II negative regulation of interleukin-2 production proteasome-mediated ubiquitin-dependent protein catabolic process regulation of T cell differentiation negative regulation of transcription, DNA-templated negative regulation of T-helper 17 cell differentiation negative regulation of T-helper 17 cell lineage commitment negative regulation of T-helper 2 cell cytokine production positive regulation of gene expression Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 30009 57765 Ensembl ENSG00000073861 ENSMUSG00000001444 UniProt Q9UL17 Q9JKD8 RefSeq (mRNA) NM_013351 NM_019507 RefSeq (protein) NP_037483 NP_062380 Location (UCSC) Chr 17: 47.73 – 47.75 Mb Chr 11: 96.99 – 97.01 Mb PubMed search
Wikidata
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Function

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.

The function of T-bet is best known in T helper cells (Th cells). In naïve Th cells the gene is not constitutively expressed, but can be induced via 2 independent signalling pathways, IFNg-STAT1 and IL-12-STAT4 pathways. Both need to cooperate to reach stable Th1 phenotype. Th1 phenotype is also stabilised by repression of regulators of other Th cell phenotypes (Th2 and Th17). In a typical scenario it is thought that IFNg and T cell receptor (TCR) signalling initiates the expression of Tbet, and once TCR signalling stops, signalling via IL-12 receptor can come to play as it was blocked by repression of expression of one of its receptor subunits (IL12Rb2) by TCR signalling. IL-2 signalling enhances the expression of IL-12R. The 2-step expression of T-bet can be viewed as a safety mechanism of sort, which ensures, that cells commit to the Th1 phenotype only when desired.

T-bet controls transcription of many genes, for example proinflammatory cytokines like lymphotoxin-a, tumour necrosis factor and ifng, which is a hallmark cytokine of type one immunity. Certain chemokines are also regulated by T-bet, namely xcl1, ccl3, ccl4 and chemokine receptors cxcr3, ccr5. The expression of T-bet controlled genes is facilitated by 2 distinct mechanisms: chromatin remodelation via enzyme recruitment and direct binding to enhancer sequences promoting transcription or 3D gene structure supporting transcription. T-bet also recruits other transcription factors like HLX, RUNX1, RUNX3 which aid it in setting Th1 transcription profile.

Apart from promoting type 1 immune response (Th1), T-bet also suppresses the other types of immune response. Type 2 immune response (Th2) phenotype is repressed by sequestering of its master regulator, GATA3 away from its target genes. Gata3 expression is further silenced by promotion of silencing epigenetic changes in its region. In addition to that the Th2 specific cytokines are also silenced by binding of T-bet and RUNX3 to il4 silencer region. Type 17 immune response (Th17) phenotype is suppressed by RUNX1 recruitment, which disallows it to mediate Th17 specific genes, like rorc, a Th17 master regulator. Rorc is also silenced by epigenetic changes promoted by T-bet and STAT4.

T-bet also performs function in cytotoxic T cells and B cells. In cytotoxic T cells it promotes IFNg, granzyme B expression and in cooperation with another transcription factor EOMES their maturation. The role of T-bet in B cells seems to be to direct the cell towards type 1 immune response expression profile, which involves secretion of antibodies IGg1 and IGg3 and is usually elevated during viral infections. These populations of B cells differ from standard ones by their lack of receptors CD21 and CD27, also given that these cells have undergone antibody class switch, they are regarded as memory B cells. These cells have been shown to secrete IFNg and in vitro to polarise naïve T helper cells towards Th1 phenotype. Populations of T-bet positive B cells were also identified in various autoimmune diseases like systemic lupus erythematosus, Crohn's disease, multiple sclerosis and rheumatoid arthritis.

Role in mucosal homeostasis

It has been identified that T-bet contributes to the maintenance of mucosal homeostasis and mucosal immune response. Mice lacking adapative immune cells and T-bet (RAG -/-, T-bet -/-) developed disease similar to human ulcerative colitis (hence the name TRUC), which was later attributed to the outgrowth Gram-negative bacteria, namely Helicobacter typhlonius. The dysbiosis appears to be a consequence of multiple factors, firstly the innate lymphoid cells 1 (ILC1) population and a subset of ILC3s are missing, because the expression of T-bet is needed for their maturation. Secondly, T-bet ablation causes increased levels of TNF, as its expression is not repressed in dendritic cells and immune system is more biased away from Th1.

Role in disease

Atherosclerosis

Atherosclerosis is an autoimmune disease caused by inflammation and associated infiltration of immune cells in fatty deposits in arteries called atherosclerosis plaques. Th1 cells are responsible for production of proinflammatory cytokines contributing to the progression of the disease by promoting expression of adhesive (e.g., ICAM1) and homing molecules (mainly CCR5) needed for cellular migration. Experimental vaccination of patients with peptides derived from apolipoprotein B, part of low-density lipoprotein, which is deposited on arterial walls, has shown increased T regulatory cells (TREGs) and cytotoxic T cells. The vaccination has showed smaller Th1 differentiation, though the mechanism behind it remains unresolved. Currently it is hypothesised that the decrease of Th1 differentiation is caused by the destruction of dendritic cells presenting auto antigens by cytotoxic T cells and increased differentiation of TREGs suppressing immune response. Taken together T-bet might serve as a potential target in treatment of atherosclerosis.

Asthma

The transcription factor encoded by TBX21 is T-bet, which regulates the development of naive T lymphocytes. Asthma is a disease of chronic inflammation, and it is known that transgenic mice born without TBX21 spontaneously develop abnormal lung function consistent with asthma. It is thought that TBX21, therefore, may play a role in the development of asthma in humans as well.

Experimental autoimmune encephalomyelitis

Initially it was thought that experimental autoimmune encephalomyelitis (EAE) is caused by autoreactive Th1 cells. T-bet-deficient mice were resistant to EAE. However, later research has discovered, that not only Th1 but also Th17 and ThGM-CSF cells are the cause of immunopathology. Interestingly, IFNg, a main product of T-bet, has shown bidirectional effect in EAE. Injection of IFNg during acute stage worsens the course of the disease, presumably by strengthening Th1 response, however injection of IFNg in chronic stage has shown suppressive effect on EAE symptoms. Currently it is thought that IFNg stops T helper cells from committing for example to the Th17 phenotype, stimulates indoleamine 2,3-dioxygenase transcription (kynurenines or kyn pathway) in certain dendritic cells, stimulates cytotoxic T cells, downregulates T cell trafficking and limits their survival. T-bet and its controlled genes remain a possible target in treatment of neurological autoimmune diseases.

Further reading

• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (March 2000). "A novel transcription factor, T-bet, directs Th1 lineage commitment". Cell. 100 (6): 655–669. doi:10.1016/S0092-8674(00)80702-3. PMID 10761931. S2CID 14326322.
• Zhang WX, Yang SY (November 2000). "Cloning and characterization of a new member of the T-box gene family". Genomics. 70 (1): 41–48. doi:10.1006/geno.2000.6361. PMID 11087660.
• Faedo A, Ficara F, Ghiani M, Aiuti A, Rubenstein JL, Bulfone A (August 2002). "Developmental expression of the T-box transcription factor T-bet/Tbx21 during mouse embryogenesis". Mechanisms of Development. 116 (1–2): 157–160. doi:10.1016/S0925-4773(02)00114-4. PMID 12128215. S2CID 14925626.
• Chung HT, Kim LH, Park BL, Lee JH, Park HS, Choi BW, et al. (September 2003). "Association analysis of novel TBX21 variants with asthma phenotypes". Human Mutation. 22 (3): 257. doi:10.1002/humu.9169. PMID 12938094. S2CID 21977810.
• Yu HR, Chang JC, Chen RF, Chuang H, Hong KC, Wang L, Yang KD (November 2003). "Different antigens trigger different Th1/Th2 reactions in neonatal mononuclear cells (MNCs) relating to T-bet/GATA-3 expression". Journal of Leukocyte Biology. 74 (5): 952–958. doi:10.1189/jlb.0902474. PMID 12960249. S2CID 39107628.
• Lametschwandtner G, Biedermann T, Schwärzler C, Günther C, Kund J, Fassl S, et al. (May 2004). "Sustained T-bet expression confers polarized human TH2 cells with TH1-like cytokine production and migratory capacities". The Journal of Allergy and Clinical Immunology. 113 (5): 987–994. doi:10.1016/j.jaci.2004.02.004. PMID 15131585.
• Sasaki Y, Ihara K, Matsuura N, Kohno H, Nagafuchi S, Kuromaru R, et al. (August 2004). "Identification of a novel type 1 diabetes susceptibility gene, T-bet". Human Genetics. 115 (3): 177–184. doi:10.1007/s00439-004-1146-2. PMID 15241679. S2CID 32348097.
• Tantisira KG, Hwang ES, Raby BA, Silverman ES, Lake SL, Richter BG, et al. (December 2004). "TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids". Proceedings of the National Academy of Sciences of the United States of America. 101 (52): 18099–18104. Bibcode:2004PNAS..10118099T. doi:10.1073/pnas.0408532102. PMC 539815. PMID 15604153.
• Atayar C, Poppema S, Blokzijl T, Harms G, Boot M, van den Berg A (January 2005). "Expression of the T-cell transcription factors, GATA-3 and T-bet, in the neoplastic cells of Hodgkin lymphomas". The American Journal of Pathology. 166 (1): 127–134. doi:10.1016/S0002-9440(10)62238-9. PMC 1602286. PMID 15632006.
• Tong Y, Aune T, Boothby M (February 2005). "T-bet antagonizes mSin3a recruitment and transactivates a fully methylated IFN-gamma promoter via a conserved T-box half-site". Proceedings of the National Academy of Sciences of the United States of America. 102 (6): 2034–2039. Bibcode:2005PNAS..102.2034T. doi:10.1073/pnas.0409510102. PMC 548570. PMID 15684083.
• Dorfman DM, Hwang ES, Shahsafaei A, Glimcher LH (January 2005). "T-bet, a T cell-associated transcription factor, is expressed in Hodgkin's lymphoma". Human Pathology. 36 (1): 10–15. doi:10.1016/j.humpath.2004.10.006. PMID 15712176.
• Kulkarni A, Ravi DS, Singh K, Rampalli S, Parekh V, Mitra D, Chattopadhyay S (April 2005). "HIV-1 Tat modulates T-bet expression and induces Th1 type of immune response". Biochemical and Biophysical Research Communications. 329 (2): 706–712. doi:10.1016/j.bbrc.2005.02.042. PMID 15737643.
• Akahoshi M, Obara K, Hirota T, Matsuda A, Hasegawa K, Takahashi N, et al. (June 2005). "Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma". Human Genetics. 117 (1): 16–26. doi:10.1007/s00439-005-1285-0. PMID 15806396. S2CID 23920947.
• Kawana K, Kawana Y, Schust DJ (August 2005). "Female steroid hormones use signal transducers and activators of transcription protein-mediated pathways to modulate the expression of T-bet in epithelial cells: a mechanism for local immune regulation in the human reproductive tract". Molecular Endocrinology. 19 (8): 2047–2059. doi:10.1210/me.2004-0489. PMID 15860546. S2CID 31585846.
• Harashima A, Matsuo Y, Drexler HG, Okochi A, Motoda R, Tanimoto M, Orita K (July 2005). "Transcription factor expression in B-cell precursor-leukemia cell lines: preferential expression of T-bet". Leukemia Research. 29 (7): 841–848. doi:10.1016/j.leukres.2004.12.010. PMID 15927679.
• Deng Y, Kerdiles Y, Chu J, Yuan S, Wang Y, Chen X, et al. (March 2015). "Transcription factor Foxo1 is a negative regulator of natural killer cell maturation and function". Immunity. 42 (3): 457–470. doi:10.1016/j.immuni.2015.02.006. PMC 4400836. PMID 25769609.
• Raby BA, Hwang ES, Van Steen K, Tantisira K, Peng S, Litonjua A, et al. (January 2006). "T-bet polymorphisms are associated with asthma and airway hyperresponsiveness". American Journal of Respiratory and Critical Care Medicine. 173 (1): 64–70. doi:10.1164/rccm.200503-505OC. PMC 2662983. PMID 16179640.

External links

• TBX21 protein, human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)