T-box transcription factor TBX21, also called T-bet (T-box expressed in T cells) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''TBX21''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. 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.

Function

This gene is a member of a phylogenetically conserved family of genes that share a common

DNA-binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a gener ...

, the

T-box T-box refers to a group of transcription factors involved in embryonic limb and heart development. Every T-box protein has a relatively large DNA-binding domain, generally comprising about a third of the entire protein that is both necessary a ...

. T-box genes encode

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

s 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 The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...

-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 cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...

s (Th cells). In naïve Th cells the gene is not constitutively expressed, but can be induced via 2 independent signalling pathways, IFNg-

STAT1 Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family. Function All STAT molecules are phosphorylated by receptor associ ...

and IL-12-

STAT4 Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind ...

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 T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg different ...

). 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 Chemokine (C-C motif) ligand 3 (CCL3) also known as macrophage inflammatory protein 1-alpha (MIP-1-alpha) is a protein that in humans is encoded by the ''CCL3'' gene. Function CCL3 is a cytokine belonging to the CC chemokine family that is i ...

'', ''

ccl4 Chemokine (C-C motif) ligands 4 (also CCL4) previously known as macrophage inflammatory protein (MIP-1β), is a protein which in humans is encoded by the ''CCL4'' gene. ''CCL4'' belongs to a cluster of genes located on 17q11-q21 of the chromosom ...

'' and

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...

receptors ''

cxcr3 Chemokine receptor CXCR3 is a Gαi protein-coupled receptor in the CXC chemokine receptor family. Other names for CXCR3 are G protein-coupled receptor 9 (GPR9) and CD183. There are three isoforms of CXCR3 in humans: CXCR3-A, CXCR3-B and chemokin ...

'', ''

ccr5 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. In humans, the ''CCR5'' gene that encodes the CCR5 p ...

''. 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 In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...

like HLX,

RUNX1 Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the ''RUNX1'' gene. RUNX1 is a transcription factor that re ...

RUNX3 Runt-related transcription factor 3 is a protein that in humans is encoded by the ''RUNX3'' gene. Function This gene encodes a member of the runt domain-containing family of transcription factors. A heterodimer of this protein and a beta subu ...

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 GATA3 is a transcription factor that in humans is encoded by the ''GATA3'' gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes. The GATA3 transcription ...

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

to '' il4'' silencer region. Type 17 immune response (

) phenotype is suppressed by

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

. T-bet also performs function in

cytotoxic T cells A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular p ...

and

B cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...

. In cytotoxic T cells it promotes IFNg,

granzyme B Granzyme B (GrB) is one of the serine protease granzymes most commonly found in the granules of natural killer cells (NK cells) and cytotoxic T cells. It is secreted by these cells along with the pore forming protein perforin to mediate apoptosi ...

expression and in cooperation with another transcription factor EOMES their maturationThe 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 Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

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 Rag, rags, RAG or The Rag may refer to: Common uses * Rag, a piece of old cloth * Rags, tattered clothes * Rag (newspaper), a publication engaging in tabloid journalism * Rag paper, or cotton paper Arts and entertainment Film * ''Rags'' (1915 ...

-/-, T-bet -/-) developed disease similar to human

ulcerative colitis Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and ...

(hence the name TRUC), which was later attributed to the outgrowth

Gram-negative bacteria Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

, 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 Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

, as its expression is not repressed in

dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...

and immune system is more biased away from Th1.

Role in disease

Atherosclerosis

Atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...

is an autoimmune disease caused by inflammation and associated infiltration of immune cells in fatty deposits in

arteries An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...

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 ICAM-1 (Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ''ICAM1'' gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial ...

) and homing molecules (mainly

CCR5 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. In humans, the ''CCR5'' gene that encodes the CCR5 p ...

) needed for cellular migration. Experimental vaccination of patients with peptides derived from

apolipoprotein B Apolipoprotein B (ApoB) is a protein that in humans is encoded by the gene. Function Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, Lp(a), IDL, and LDL particles (LDL—commonly known as "bad cholesterol" when in ref ...

, part of

low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall dens ...

, which is deposited on arterial walls, has shown increased

T regulatory cells T, or t, is the twentieth letter in the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''tee'' (pronounced ), plural ''tees''. It is der ...

(TREGs) and

. 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

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 A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

. 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 Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with r ...

(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

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 The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...

from committing for example to the Th17 phenotype, stimulates

indoleamine 2,3-dioxygenase Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO ) is a heme-containing enzyme physiologically expressed in a number of tissues and cells, such as the small intestine, lungs, female genital tract or placenta. In humans is encoded by the ''IDO1' ...

transcription (kynurenines or kyn pathway) in certain

, stimulates

, downregulates T cell trafficking and limits their survival. T-bet and its controlled genes remain a possible target in treatment of neurological autoimmune diseases.

References

External links

* {{Transcription factors, g4 Transcription factors