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. [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 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. [5]
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. [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, 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. [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 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. [6]
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 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. [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 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. [9]
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. [7]
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. [10]
Initially it was thought that experimental autoimmune encephalomyelitis (EAE) is caused by autoreactive Th1 cells. T-bet-deficient mice were resistant to EAE. [11] 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. [12]
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 considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.
Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.
Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.
The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene.
Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.
Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells but has since been found to play an important role in regulating many more body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.
Interleukin 27 (IL-27) is a member of the IL-12 cytokine family. It is a heterodimeric cytokine that is encoded by two distinct genes, Epstein-Barr virus-induced gene 3 (EBI3) and IL-27p28. IL-27 is expressed by antigen presenting cells and interacts with a specific cell-surface receptor complex known as IL-27 receptor (IL-27R). This receptor consists of two proteins, IL-27Rɑ and gp130. IL-27 induces differentiation of the diverse populations of T cells in the immune system and also upregulates IL-10.
Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.
Understanding of the antitumor immunity role of CD4+ T cells has grown substantially since the late 1990s. CD4+ T cells (mature T-helper cells) play an important role in modulating immune responses to pathogens and tumor cells, and are important in orchestrating overall immune responses.
Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient. STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12. There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma production downstream.
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 actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.
Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.
T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.
Interleukin 1 receptor-like 1, also known as IL1RL1 and ST2, is a protein that in humans is encoded by the IL1RL1 gene.
Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.
Regulatory B cells (Bregs or Breg cells) represent a small population of B cells that participates in immunomodulation and in the suppression of immune responses. The population of Bregs can be further separated into different human or murine subsets such as B10 cells, marginal zone B cells, Br1 cells, GrB+B cells, CD9+ B cells, and even some plasmablasts or plasma cells. Bregs regulate the immune system by different mechanisms. One of the main mechanisms is the production of anti-inflammatory cytokines such as interleukin 10 (IL-10), IL-35, or transforming growth factor beta (TGF-β). Another known mechanism is the production of cytotoxic Granzyme B. Bregs also express various inhibitory surface markers such as programmed death-ligand 1 (PD-L1), CD39, CD73, and aryl hydrocarbon receptor. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions, and in anti-tumor immunity.
In cell biology, TH9 cells are a sub-population of CD4+T cells that produce interleukin-9 (IL-9). They play a role in defense against helminth infections, in allergic responses, in autoimmunity, and tumor suppression.
Type 3 innate lymphoid cells (ILC3) are immune cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-commensal mutualism and pathogen clearance. They are part of a heterogeneous group of innate lymphoid cells, which is traditionally divided into three subsets based on their expression of master transcription factors as well as secreted effector cytokines - ILC1, ILC2 and ILC3.
Th17 pathogenic refers to a distinct phenotype of Th17 cells which is associated with immunopathology. The development of the pathogenic phenotype can be shaped by various environmental stimuli and genetic factors. In humans, Th17 pathogenic cells are associated with diseases like multiple sclerosis (MS) or rheumatoid arthritis (RA) and in mice with experimental autoimmune encephalomyelitis (EAE). Th17 pathogenic cells are known to display pro-inflammatory features like expressing transcription factor T-bet and secreting cytokine IFNγ, resembling Th1-like phenotype. Th17 cells are a very heterogenous subset and can switch to display all T helper-like phenotype markers including those typical for Th2, Treg and Tfh.
