T-box transcription factor TBX21, also called T-bet (T-box expressed in T cells), is aprotein that in humans is encoded by theTBX21gene.[5] 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.[6]
This gene is a member of a phylogenetically conserved family of genes that share a commonDNA-binding domain, theT-box. T-box genes encodetranscription 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 aTh1 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.[5]
The function of T-bet is best known inT 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 andIL-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 andTh17). In a typical scenario it is thought that IFNg and T cell receptor (TCR) signalling initiates the expression ofTbet, 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.[6]
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.[7][6] Certain chemokines are also regulated by T-bet, namelyxcl1,ccl3,ccl4 andchemokine receptorscxcr3,ccr5. The expression of T-bet controlled genes is facilitated by 2 distinct mechanisms:chromatin remodelation via enzyme recruitment and direct binding toenhancer sequences promoting transcription or 3D gene structure supporting transcription. T-bet also recruits othertranscription factors likeHLX,RUNX1,RUNX3 which aid it in setting Th1 transcription profile.[6]
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 silencingepigenetic changes in its region. In addition to that the Th2 specific cytokines are also silenced by binding of T-bet andRUNX3 toil4 silencer region. Type 17 immune response (Th17) phenotype is suppressed byRUNX1 recruitment, which disallows it to mediate Th17 specific genes, likerorc, a Th17 master regulator.Rorc is also silenced by epigenetic changes promoted by T-bet andSTAT4.[6]
T-bet also performs function incytotoxic T cells andB cells. In cytotoxic T cells it promotesIFNg,granzyme B expression and in cooperation with another transcription factorEOMES 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 ofantibodies 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 likesystemic lupus erythematosus,Crohn's disease,multiple sclerosis andrheumatoid arthritis.[8]
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 humanulcerative colitis (hence the name TRUC), which was later attributed to the outgrowthGram-negative bacteria, namelyHelicobacter 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 ofTNF, as its expression is not repressed indendritic cells and immune system is more biased away from Th1.[9]
Atherosclerosis is an autoimmune disease caused by inflammation and associated infiltration of immune cells in fatty deposits inarteries called atherosclerosis plaques. Th1 cells are responsible for production of proinflammatorycytokines contributing to the progression of the disease by promoting expression of adhesive (e.g.,ICAM1) and homing molecules (mainlyCCR5) needed for cellular migration. Experimental vaccination of patients with peptides derived fromapolipoprotein B, part oflow-density lipoprotein, which is deposited on arterial walls, has shown increasedT regulatory cells (TREGs) andcytotoxic T cells. The vaccination has showed smallerTh1 differentiation, though the mechanism behind it remains unresolved. Currently it is hypothesised that the decrease of Th1 differentiation is caused by the destruction ofdendritic cells presenting autoantigens 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.[7]
The transcription factor encoded by TBX21 is T-bet, which regulates the development of naiveT 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.[10]
Initially it was thought thatexperimental autoimmune encephalomyelitis (EAE) is caused by autoreactiveTh1 cells. T-bet-deficient mice were resistant to EAE.[11] However, later research has discovered, that not only Th1 but alsoTh17 andThGM-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 stopsT helper cells from committing for example to the Th17 phenotype, stimulatesindoleamine 2,3-dioxygenase transcription (kynurenines orkyn pathway) in certaindendritic cells, stimulatescytotoxic 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.[12]
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