| TOX | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | TOX , TOX1, thymocyte selection associated high mobility group box | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 606863 MGI: 2181659 HomoloGene: 8822 GeneCards: TOX | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Thymocyte selection-associated high mobility group box protein TOX is a protein that in humans is encoded by the TOX gene. [5] [6] [7] TOX drives T-cell exhaustion [8] [9] and plays a role in innate lymphoid cell development. [10] [11]
The TOX gene encodes a protein that belongs to a large superfamily of chromatin associated proteins that share an approximately 75 amino acid DNA binding motif, the HMG (high mobility group)-box (named after that found in the canonical member of the family, high mobility group protein 1). Some high mobility group (HMG) box proteins (e.g., LEF1) contain a single HMG box motif and bind DNA in a sequence-specific manner, while other members of this family (e.g., HMGB1) have multiple HMG boxes and bind DNA in a sequence-independent but structure-dependent manner. While TOX has a single HMG-box motif, [7] it is predicted to bind DNA in a sequence-independent manner. [12]
TOX is a member of a small subfamily of proteins (TOX2, TOX3, and TOX4) that share almost identical HMG-box sequences. [12] TOX2 has been identified to play a role in the differentiation of T follicular helper cell. [13] TOX2 is thought to be a downstream signal of BCL-6. [13] TOX3 has been identified as a breast cancer susceptibility locus. [14] [15] TOX is highly expressed in the thymus, the site of development of T lymphocytes. [10] Knockout mice that lack TOX have a severe defect in development of certain subsets of T lymphocytes. [16]
TOX is necessary for T cell persistence but also drives T cell exhaustion. [17] [18] [19] An increase in TOX expression is characterized by a weakening of the effector functions of the cytotoxic T cell and upregulation of inhibitory receptors on the cytotoxic T cells. [20] [21] TOX promotes the exhausted T cell phenotype through epigenetic remodeling. [20] [22] PD-1 is an inhibitory marker on T cells that increases when TOX is unregulated. [20] [23] [22] This allows for cancerous cells to evade the cytotoxic T cells through upregulated expression of PD-L1. [24]
Markers of effector functions that are decreased when TOX is overexpressed are KLRG1, TNF, and IFN-gamma. [8] IFN-gamma and TNF-alpha production are also increased when the Tox and Tox2 genes are deleted. [9] Upregulation of effector function in cells lacking TOX is not always seen and it has been proposed that inhibitory receptor function is separated from effector CD8+ cytotoxic T cell function. [8] T-cell exhaustion does not occur when TOX is deleted from CD8+ T cells, but the cells instead adopt the KLRG1+ terminal effector state and undergo apoptosis, or programmed cell death. [9] It was therefore proposed that TOX prevents this terminal differentiation and instead promotes exhaustion so that the T-cell has a slightly more sustained response. [9]
In cancer or during chronic viral infection, T-cell exhaustion occurs when cytotoxic T-cells are constantly stimulated. [8] [25] TOX is upregulated in CD8+ T cells from chronic infection when compared to acute infection. [8] Patients with cancer typically have high levels of TOX in their tumor-infiltrating lymphocytes, [8] and anti-tumor immunity is heightened when Tox and Tox2 are deleted. [9] TOX and TOX2-deficient tumor-specific CAR T cells additionally have increased antitumor effector cell function as well as decreased levels of inhibitory receptors. [8]
NFAT transcription factors are essential for activating TOX in CD8+ T-cells, [8] and it has been suggested that TOX is a downstream target of NFAT. [9] The expression and function of NR4a (a target of NFAT) and TOX are strongly linked with reduced NR4a expression in Tox double knockout T cells and minimized Tox expression in NR4a triple knockout T cells. [9]
TOX is necessary for positive selection in developing thymocytes. [26] Knock out TOX mice shows a requirement of TOX for the CD4 T cell lineage, [26] however CD8 single positive T-cells were still able to develop. [26]
TOX is necessary for the development of innate lymphoid cells. [10] [11] Innate lymphoid cells include ILC1, ILC2, ILC3 and NK cells. [26]
Notch signaling can aid in the development of all innate lymphoid cells, but in TOX-deficient cells, Notch target genes are expressed at low levels, so it is possible that TOX is required for downstream activation of these Notch target genes. [10] TOX was also found to bind Hes1, a Notch target gene, in embryonic kidney cells. [10]
Several ILC3 populations are reduced in the absence of TOX, implicating TOX’s role in their development. [10] In the small intestine, major ILC3 populations are normal in TOX-deficient cells, suggesting that gut ILC3 development may occur independently of TOX. [10] Some ILC3 populations in the gut expand in the absence of TOX. [10]
It has been proposed that NFIL3 and TOX regulate the transition of common lymphoid progenitor to early innate lymphoid progenitor. [11] In NFIL3-deficient mice, the expression of TOX is downregulated, indicating that NFIL3 is directly affecting the expression of TOX which is then acting downstream in ILC development. [11] TOX-deficient mice and NFIL3-deficient mice both lack mature ILCs and ILC progenitors. [11]
T cells are one of the important types of 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 receptor (TCR) on their cell surface.
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.
A leucine zipper is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amino acid segment and the display of these amino acid sequences on an idealized alpha helix revealed a periodic repetition of leucine residues at every seventh position over a distance covering eight helical turns. The polypeptide segments containing these periodic arrays of leucine residues were proposed to exist in an alpha-helical conformation and the leucine side chains from one alpha helix interdigitate with those from the alpha helix of a second polypeptide, facilitating dimerization.
Lck is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T-cell receptor signaling in both naive T cells and effector T cells. The role of the Lck is less prominent in the activation or in the maintenance of memory CD8 T cells in comparison to CD4 T cells. In addition, the role of the lck varies among the memory T cells subsets. It seems that in mice, in the effector memory T cells (TEM) population, more than 50% of lck is present in a constitutively active conformation, whereas, only less than 20% of lck is present as active form of lck. These differences are due to differential regulation by SH2 domain–containing phosphatase-1 (Shp-1) and C-terminal Src kinase.
CD3 is a protein complex and T cell co-receptor that is involved in activating both the cytotoxic T cell and T helper cells. It is composed of four distinct chains. In mammals, the complex contains a CD3γ chain, a CD3δ chain, and two CD3ε chains. These chains associate with the T-cell receptor (TCR) and the CD3-zeta (ζ-chain) to generate an activation signal in T lymphocytes. The TCR, CD3-zeta, and the other CD3 molecules together constitute the TCR complex.
RAR-related orphan receptor alpha (RORα), also known as NR1F1 is a nuclear receptor that in humans is encoded by the RORA gene. RORα participates in the transcriptional regulation of some genes involved in circadian rhythm. In mice, RORα is essential for development of cerebellum through direct regulation of genes expressed in Purkinje cells. It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient. In addition, although present in normal numbers, the ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production.
C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21). The ligands have similar affinity for the receptor, though CCL19 has been shown to induce internalisation of CCR7 and desensitisation of the cell to CCL19/CCL21 signals. CCR7 is a transmembrane protein with 7 transmembrane domains, which is coupled with heterotrimeric G proteins, which transduce the signal downstream through various signalling cascades. The main function of the receptor is to guide immune cells to immune organs by detecting specific chemokines, which these tissues secrete.
RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC gene. RORγ is a member of the nuclear receptor family of transcription factors. It is mainly expressed in immune cells and it also regulates circadian rhythms. It may be involved in the progression of certain types of cancer.
SATB1 is a protein which in humans is encoded by the SATB1 gene. It is a dimeric/tetrameric transcription factor with multiple DNA binding domains. SATB1 specifically binds to AT-rich DNA sequences with high unwinding propensity called base unpairing regions (BURs), containing matrix attachment regions (MARs).
HMG-box transcription factor 1, also known as HBP1, is a human protein.
Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3)gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.
Zinc finger protein Helios is a protein that in humans is encoded by the IKZF2 gene. This protein is a member of Ikaros family of transcription factors.
Interleukin-2 receptor alpha chain is a protein involved in assembly of high-affinity Interleukin-2 receptor, consisting of alpha (IL2RA), beta (IL2RB) and the common gamma chain (IL2RG). As the name indicates, this receptor interacts with pleiotropic cytokine called Interleukin-2, which effect is mainly important for immune homeostasis.
TOX high mobility group box family member 3, also known as TOX3, is a human gene.
Mucosal immunology is the study of immune system responses that occur at mucosal membranes of the intestines, the urogenital tract, and the respiratory system. The mucous membranes are in constant contact with microorganisms, food, and inhaled antigens. In healthy states, the mucosal immune system protects the organism against infectious pathogens and maintains a tolerance towards non-harmful commensal microbes and benign environmental substances. Disruption of this balance between tolerance and deprivation of pathogens can lead to pathological conditions such as food allergies, irritable bowel syndrome, susceptibility to infections, and more.
NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.
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Tissue-resident memory T cells or TRM cells represent a subset of a long-lived memory T cells that occupies epithelial and mucosal tissues without recirculating. TRM cells are transcriptionally, phenotypically and functionally distinct from central memory (TCM) and effector memory (TEM) T cells which recirculate between blood, the T cell zones of secondary lymphoid organ, lymph and nonlymphoid tissues. Moreover, TRM cells themself represent a diverse populations because of the specializations for the resident tissues. The main role of TRM cells is to provide superior protection against infection in extralymphoid tissues.
Anjana Rao is a cellular and molecular biologist of Indian ethnicity, working in the US. She uses immune cells as well as other types of cells to understand intracellular signaling and gene expression. Her research focuses on how signaling pathways control gene expression.
Patrick G. Hogan is a cellular and molecular biologist who studies how cellular signaling leads to gene expression. He obtained his bachelor’s degree from Harvard University and a PhD in neurobiology from Harvard Medical School. In 2010, he moved to the La Jolla Institute for Immunology in San Diego as a Professor in the Division of Signaling and Gene Expression. He is a Founder and Member of the Scientific Advisory Board, CalciMedica Inc, La Jolla, CA.
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