[{"@context":"http:\/\/schema.org\/","@type":"BlogPosting","@id":"https:\/\/wiki.edu.vn\/en\/wiki24\/tox-wikipedia\/#BlogPosting","mainEntityOfPage":"https:\/\/wiki.edu.vn\/en\/wiki24\/tox-wikipedia\/","headline":"TOX &#8211; Wikipedia","name":"TOX &#8211; Wikipedia","description":"before-content-x4 From Wikipedia, the free encyclopedia after-content-x4 Protein-coding gene in the species Homo sapiens Thymocyte selection-associated high mobility group box","datePublished":"2021-06-22","dateModified":"2021-06-22","author":{"@type":"Person","@id":"https:\/\/wiki.edu.vn\/en\/wiki24\/author\/lordneo\/#Person","name":"lordneo","url":"https:\/\/wiki.edu.vn\/en\/wiki24\/author\/lordneo\/","image":{"@type":"ImageObject","@id":"https:\/\/secure.gravatar.com\/avatar\/c9645c498c9701c88b89b8537773dd7c?s=96&d=mm&r=g","url":"https:\/\/secure.gravatar.com\/avatar\/c9645c498c9701c88b89b8537773dd7c?s=96&d=mm&r=g","height":96,"width":96}},"publisher":{"@type":"Organization","name":"Enzyklop\u00e4die","logo":{"@type":"ImageObject","@id":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","url":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","width":600,"height":60}},"image":{"@type":"ImageObject","@id":"https:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/c\/cb\/TOX_Pathway.png\/220px-TOX_Pathway.png","url":"https:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/c\/cb\/TOX_Pathway.png\/220px-TOX_Pathway.png","height":"88","width":"220"},"url":"https:\/\/wiki.edu.vn\/en\/wiki24\/tox-wikipedia\/","wordCount":9841,"articleBody":"     (adsbygoogle = window.adsbygoogle || []).push({});before-content-x4From Wikipedia, the free encyclopedia       (adsbygoogle = window.adsbygoogle || []).push({});after-content-x4Protein-coding gene in the species Homo sapiens  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]       (adsbygoogle = window.adsbygoogle || []).push({});after-content-x4Table of ContentsStructure[edit]TOX subfamily[edit]Function[edit]T cell exhaustion[edit]Effector function[edit]Cancer &#038; chronic infection[edit]Activation[edit]T-cell development[edit]Innate lymphoid cells development[edit]References[edit]Further reading[edit]Structure[edit]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 subfamily[edit]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]       (adsbygoogle = window.adsbygoogle || []).push({});after-content-x4Function[edit]T cell exhaustion[edit]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]Effector function[edit]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]Cancer &#038; chronic infection[edit]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]Activation[edit]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]T-cell development[edit]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]Innate lymphoid cells development[edit]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\u2019s 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]References[edit]^ a b c GRCh38: Ensembl release 89: ENSG00000198846 &#8211; Ensembl, May 2017^ a b c GRCm38: Ensembl release 89: ENSMUSG00000041272 &#8211; Ensembl, May 2017^ &#8220;Human PubMed Reference:&#8221;. National Center for Biotechnology Information, U.S. National Library of Medicine.^ &#8220;Mouse PubMed Reference:&#8221;. National Center for Biotechnology Information, U.S. National Library of Medicine.^ Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A,  et\u00a0al. (October 1998). &#8220;Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro&#8221;. DNA Research. 5 (5): 277\u2013286. doi:10.1093\/dnares\/5.5.277. PMID\u00a09872452.^ Wilkinson B, Chen JY, Han P, Rufner KM, Goularte OD, Kaye J (March 2002). &#8220;TOX: an HMG box protein implicated in the regulation of thymocyte selection&#8221;. Nature Immunology. 3 (3): 272\u2013280. doi:10.1038\/ni767. PMID\u00a011850626. S2CID\u00a019716719.^ a b &#8220;Entrez Gene: thymocyte selection-associated high mobility group box gene TOX&#8221;.^ a b c d e f g h Bordon Y (August 2019). &#8220;TOX for tired T cells&#8221;. Nature Reviews. Immunology. 19 (8): 476. doi:10.1038\/s41577-019-0193-9. PMID\u00a031243349.^ a b c d e f g Ando M, Ito M, Srirat T, Kondo T, Yoshimura A (March 2020). &#8220;Memory T cell, exhaustion, and tumor immunity&#8221;. Immunological Medicine. 43 (1): 1\u20139. doi:10.1080\/25785826.2019.1698261. PMID\u00a031822213.^ a b c d e f g h Seehus CR, Kaye J (2015). &#8220;The Role of TOX in the Development of Innate Lymphoid Cells&#8221;. Mediators of Inflammation. 2015: 243868. doi:10.1155\/2015\/243868. PMC\u00a04628649. PMID\u00a026556952.^ a b c d e Stokic-Trtica V, Diefenbach A, Klose CS (2020). &#8220;NK Cell Development in Times of Innate Lymphoid Cell Diversity&#8221;. Frontiers in Immunology. 11: 813. doi:10.3389\/fimmu.2020.00813. PMC\u00a07360798. PMID\u00a032733432.^ a b O&#8217;Flaherty E, Kaye J (April 2003). &#8220;TOX defines a conserved subfamily of HMG-box proteins&#8221;. BMC Genomics. 4 (1): 13. doi:10.1186\/1471-2164-4-13. PMC\u00a0155677. PMID\u00a012697058.^ a b Minton K (January 2020). &#8220;TOX2 helping hand for TFH cells&#8221;. Nature Reviews. Immunology. 20 (1): 4\u20135. doi:10.1038\/s41577-019-0249-x. PMID\u00a031745259. S2CID\u00a0208145693.^ Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG,  et\u00a0al. (June 2007). &#8220;Genome-wide association study identifies novel breast cancer susceptibility loci&#8221;. Nature. 447 (7148): 1087\u20131093. Bibcode:2007Natur.447.1087E. doi:10.1038\/nature05887. PMC\u00a02714974. PMID\u00a017529967.^ Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA,  et\u00a0al. (July 2007). &#8220;Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer&#8221;. Nature Genetics. 39 (7): 865\u2013869. doi:10.1038\/ng2064. PMID\u00a017529974. S2CID\u00a07346190.^ Aliahmad P, Kaye J (January 2008). &#8220;Development of all CD4 T lineages requires nuclear factor TOX&#8221;. The Journal of Experimental Medicine. 205 (1): 245\u2013256. doi:10.1084\/jem.20071944. PMC\u00a02234360. PMID\u00a018195075.^ Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P,  et\u00a0al. (July 2019). &#8220;TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection&#8221;. Nature. 571 (7764): 265\u2013269. doi:10.1038\/s41586-019-1326-9. PMID\u00a031207605. S2CID\u00a0190528786.^ Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP,  et\u00a0al. (July 2019). &#8220;TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion&#8221;. Nature. 571 (7764): 211\u2013218. doi:10.1038\/s41586-019-1325-x. PMC\u00a06713202. PMID\u00a031207603.^ Scott AC, D\u00fcndar F, Zumbo P, Chandran SS, Klebanoff CA, Shakiba M,  et\u00a0al. (July 2019). &#8220;TOX is a critical regulator of tumour-specific T cell differentiation&#8221;. Nature. 571 (7764): 270\u2013274. doi:10.1038\/s41586-019-1324-y. PMC\u00a07698992. PMID\u00a031207604. S2CID\u00a0190538130.^ a b c Bordon Y (August 2019). &#8220;TOX for tired T cells&#8221;. Nature Reviews. Immunology. 19 (8): 476. doi:10.1038\/s41577-019-0193-9. PMID\u00a031243349. S2CID\u00a0195657349.^ Blank CU, Haining WN, Held W, Hogan PG, Kallies A, Lugli E,  et\u00a0al. (November 2019). &#8220;Defining &#8216;T cell exhaustion&#8217;&#8220;. Nature Reviews. Immunology. 19 (11): 665\u2013674. doi:10.1038\/s41577-019-0221-9. PMC\u00a07286441. PMID\u00a031570879.^ a b Cheng Y, Shao Z, Chen L, Zheng Q, Zhang Q, Ding W,  et\u00a0al. (January 2021). &#8220;Role, function and regulation of the thymocyte selection-associated high mobility group box protein in CD8+ T cell exhaustion&#8221;. Immunology Letters. 229: 1\u20137. doi:10.1016\/j.imlet.2020.11.004. PMID\u00a033186634. S2CID\u00a0226948315.^ Kim K, Park S, Park SY, Kim G, Park SM, Cho JW,  et\u00a0al. (February 2020). &#8220;Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer&#8221;. Genome Medicine. 12 (1): 22. doi:10.1186\/s13073-020-00722-9. PMC\u00a07048139. PMID\u00a032111241.^ van der Leun AM, Thommen DS, Schumacher TN (April 2020). &#8220;CD8+ T cell states in human cancer: insights from single-cell analysis&#8221;. Nature Reviews. Cancer. 20 (4): 218\u2013232. doi:10.1038\/s41568-019-0235-4. PMC\u00a07115982. PMID\u00a032024970.^ Philip M, Schietinger A (July 2021). &#8220;CD8+ T cell differentiation and dysfunction in cancer&#8221;. Nature Reviews. Immunology. 22 (4): 209\u2013223. doi:10.1038\/s41577-021-00574-3. PMC\u00a09792152. PMID\u00a034253904. S2CID\u00a0235808117.^ a b c d Aliahmad P, Seksenyan A, Kaye J (April 2012). &#8220;The many roles of TOX in the immune system&#8221;. Current Opinion in Immunology. 24 (2): 173\u2013177. doi:10.1016\/j.coi.2011.12.001. PMC\u00a03319641. PMID\u00a022209117.Further reading[edit]Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T (June 2002). &#8220;Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones&#8221;. DNA Research. 9 (3): 99\u2013106. doi:10.1093\/dnares\/9.3.99. PMID\u00a012168954.Sebastiani P, Wang L, Nolan VG, Melista E, Ma Q, Baldwin CT, Steinberg MH (March 2008). &#8220;Fetal hemoglobin in sickle cell anemia: Bayesian modeling of genetic associations&#8221;. American Journal of Hematology. 83 (3): 189\u2013195. doi:10.1002\/ajh.21048. PMID\u00a017918249. S2CID\u00a024667609.Aliahmad P, O&#8217;Flaherty E, Han P, Goularte OD, Wilkinson B, Satake M,  et\u00a0al. (April 2004). &#8220;TOX provides a link between calcineurin activation and CD8 lineage commitment&#8221;. The Journal of Experimental Medicine. 199 (8): 1089\u20131099. doi:10.1084\/jem.20040051. PMC\u00a02211890. PMID\u00a015078895.PDB gallery2co9: Solution structure of the HMG_box domain of thymus high mobility group box protein TOX from mouse       (adsbygoogle = window.adsbygoogle || []).push({});after-content-x4"},{"@context":"http:\/\/schema.org\/","@type":"BreadcrumbList","itemListElement":[{"@type":"ListItem","position":1,"item":{"@id":"https:\/\/wiki.edu.vn\/en\/wiki24\/#breadcrumbitem","name":"Enzyklop\u00e4die"}},{"@type":"ListItem","position":2,"item":{"@id":"https:\/\/wiki.edu.vn\/en\/wiki24\/tox-wikipedia\/#breadcrumbitem","name":"TOX &#8211; Wikipedia"}}]}]