{{Short description|Protein-coding gene in the species Homo sapiens}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox gene}} '''Tumor necrosis factor receptor superfamily member 18''' (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms.<ref name="Nocentini_1997">{{Cite journal | vauthors = Nocentini G, Giunchi L, Ronchetti S, Krausz LT, Bartoli A, Moraca R, Migliorati G, Riccardi C | title = A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 12 | pages = 6216–6221 | date = 1997-06-10 | pmid = 9177197 | pmc = 21029 | doi = 10.1073/pnas.94.12.6216 | language = en | bibcode = 1997PNAS...94.6216N | issn = 0027-8424 | doi-access = free }}</ref><ref>{{Cite journal | vauthors = Nocentini G, Ronchetti S, Bartoli A, Spinicelli S, Delfino D, Brunetti L, Migliorati G, Riccardi C | title = Identification of three novel mRNA splice variants of GITR | journal = Cell Death and Differentiation | volume = 7 | issue = 4 | pages = 408–410 | date = April 2000 | pmid = 10836847 | doi = 10.1038/sj.cdd.4400670 | url = https://www.nature.com/articles/4400670 | language = en | s2cid = 36076848 | issn = 1476-5403 | url-access = subscription }}</ref> GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the ''TNFRSF18'' gene at chromosome 1.<ref>{{Cite journal | vauthors = Gurney A, Marsters S, Huang A, Pitti R, Mark M, Baldwin D, Gray A, Dowd P, Brush J, Heldens S, Schow P | title = Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR | journal = Current Biology | volume = 9 | issue = 4 | pages = 215–218 | date = February 1999 | pmid = 10074428 | doi = 10.1016/S0960-9822(99)80093-1 | language = en | s2cid = 110695 | doi-access = free | bibcode = 1999CBio....9..215G }}</ref><ref name="Kwon_1999">{{Cite journal | vauthors = Kwon B, Yu KY, Ni J, Yu GL, Jang IK, Kim YJ, Xing L, Liu D, Wang SX, Kwon BS | title = Identification of a Novel Activation-inducible Protein of the Tumor Necrosis Factor Receptor Superfamily and Its Ligand | journal = The Journal of Biological Chemistry | volume = 274 | issue = 10 | pages = 6056–6061 | date = March 1999 | pmid = 10037686 | doi = 10.1074/jbc.274.10.6056 | language = en | doi-access = free }}</ref>
== Tissue distribution ==
GITR is constitutively expressed on CD25+CD4+ regulatory T cells and its expression is upregulated on all T cell subsets after activation. GITR is also expressed on murine neutrophils and NK cells.<ref name="Tian_2020">{{Cite journal | vauthors = Tian J, Zhang B, Rui K, Wang S | title = The Role of GITR/GITRL Interaction in Autoimmune Diseases | journal = Frontiers in Immunology | volume = 11 | article-number = 588682 | date = 2020-10-09 | pmid = 33163004 | pmc = 7581784 | doi = 10.3389/fimmu.2020.588682 | issn = 1664-3224 | doi-access = free }}</ref>
== Structure ==
GITR is a member of TNFR superfamily and shares high homology in cytoplasmic domain, characterized with cysteine pseudo-repeats, with other members of TNFRSF, such as CD137, OX40 or CD27.<ref name="Kwon_1999" />
== Function ==
GITR interacts with its ligand (GITRL) that is expressed on antigen-presenting cells (APC) and endothelial cells.<ref name="Tian_2020" />
=== AITR === Human activation-inducible tumor necrosis factor receptor (AITR) and its ligand, AITRL, are important costimulatory molecules in the pathogenesis of autoimmune diseases. Despite the importance of these costimulatory molecules in autoimmune disease, their role in the autoimmune reaction to herniated disc fragments has yet to be explored.<ref name="Park_2007">{{cite journal | vauthors = Park MS, Lee HM, Hahn SB, Moon SH, Kim YT, Lee CS, Jung HW, Kwon BS, Riew KD | title = The Association of the Activation-Inducible Tumor Necrosis Factor Receptor and Ligand with Lumbar Disc Herniation | journal = Yonsei Medical Journal | volume = 48 | issue = 5 | pages = 839–846 | date = Oct 2007 | pmid = 17963343 | pmc = 2628152 | doi = 10.3349/ymj.2007.48.5.839 }}</ref>
=== GITR ===
GITR was identified as a new member of the TNF receptor superfamily, by comparing gene expression in untreated and DEX-treated murine T-cell lines.<ref name="Nocentini_1997" />
GITR is co-stimulatory surface receptor for T cells and after interaction with GITRL maintain T cell activation, proliferation, cytokine production, and rescue T cells from anti-CD3-induced apoptosis. GITR can be used as Treg marker and its signaling abrogates the suppressive function of regulatory T cells. Also, GITR plays role in Treg development, as it is expressed already at CD4+CD25+Foxp3- Treg progenitors.<ref name="Tian_2020" /><ref name="Bosmans_2021" /><ref name="Kraehenbuehl_2022">{{Cite journal | vauthors = Kraehenbuehl L, Weng CH, Eghbali S, Wolchok JD, Merghoub T | title = Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways | journal = Nature Reviews. Clinical Oncology | volume = 19 | issue = 1 | pages = 37–50 | date = January 2022 | pmid = 34580473 | doi = 10.1038/s41571-021-00552-7 | url = https://www.nature.com/articles/s41571-021-00552-7 | language = en | s2cid = 237638517 | issn = 1759-4774 | url-access = subscription }}</ref><ref name="Nocentini_2007">{{Cite journal | vauthors = Nocentini G, Ronchetti S, Cuzzocrea S, Riccardi C | title = GITR/GITRL: More than an effector T cell co-stimulatory system | journal = European Journal of Immunology | volume = 37 | issue = 5 | pages = 1165–1169 | date = May 2007 | pmid = 17407102 | doi = 10.1002/eji.200636933 | url = https://onlinelibrary.wiley.com/doi/10.1002/eji.200636933 | language = en | s2cid = 24698952 | url-access = subscription }}</ref><ref name="Mahmud_2014">{{Cite journal | vauthors = Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y, Owen DL, Schenkel JM, Boomer JS, Green JM, Yagita H, Chi H | title = Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells | journal = Nature Immunology | volume = 15 | issue = 5 | pages = 473–481 | date = May 2014 | pmid = 24633226 | pmc = 4000541 | doi = 10.1038/ni.2849 | language = en | issn = 1529-2908 }}</ref>
GITR<sup>-/-</sup> mice has no developmental problem and are fertile. They have complete block in anti-CD3-induced T cell activation and decrease in regulatory T cells progenitors. After infection challenge, GTIR<sup>-/-</sup> mice developed less inflammation than WT littermates.<ref name="Nocentini_2007" /><ref>{{Cite journal | vauthors = Ronchetti S, Nocentini G, Riccardi C, Pandolfi PP | title = Role of GITR in activation response of T lymphocytes | journal = Blood | volume = 100 | issue = 1 | pages = 350–352 | date = 2002-07-01 | pmid = 12070049 | doi = 10.1182/blood-2001-12-0276 | url = https://ashpublications.org/blood/article/100/1/350/133954/Role-of-GITR-in-activation-response-of-T | language = en | s2cid = 5697969 | issn = 1528-0020 | doi-access = free }}</ref><ref name="Bosmans_2021">{{Cite journal | vauthors = Bosmans LA, Shami A, Atzler D, Weber C, Gonçalves I, Lutgens E | title = Glucocorticoid induced TNF receptor family-related protein (GITR) – A novel driver of atherosclerosis | journal = Vascular Pharmacology | volume = 139 | article-number = 106884 | date = August 2021 | pmid = 34102305 | doi = 10.1016/j.vph.2021.106884 | language = en | s2cid = 235380691 | doi-access = free }}</ref><ref name="Mahmud_2014" />
=== Signaling === GITR does not have any enzymatic activity and signaling is propagated via recruiting TRAF-family members, specifically TRAF1, TRAF2 and TRAF5, to the GITR-signaling complex. The signaling is then mediated through NF-kB and MAPK pathways. There is an evidence that GITR has unique role for CD8+ and CD4+ T cells. GITR signaling lowers the threshold for CD28 signaling on CD8+ T cells or induces expression of CD137 on CD8+ memory T cells. For CD4+ regulatory T cells, GITR signaling promotes their expansion, inhibits Treg suppressive capacity and promotes resistance of effector T cells to Treg suppression.<ref name="Bosmans_2021" /><ref name="Knee_2016">{{Cite journal | vauthors = Knee DA, Hewes B, Brogdon JL | title = Rationale for anti-GITR cancer immunotherapy | journal = European Journal of Cancer | location = Oxford, England | volume = 67 | pages = 1–10 | date = 2016-11-01 | pmid = 27591414 | doi = 10.1016/j.ejca.2016.06.028 | url = https://www.ejcancer.com/article/S0959-8049(16)32341-3/abstract | language = English | issn = 0959-8049 | doi-access = free | url-access = subscription }}</ref>
== Clinical significance == GITR is in high interest as one of the immune checkpoint molecules that have potential in cancer treatment. GITR signaling can promote antitumor and anti-infective immune response, but also can be a driver of autoimmune diseases. Different response to GITR signaling rely on the GITR expression on different immune cell types. How GITR signaling is modulated in the different cells remains unknown. GITR agonistic antibodies are in the clinical trials as activators of effector CD8 T cells, while decreasing number of circulating suppressive regulatory T cells. Limited response to GITR agonistic antibodies is enhanced in combination with anti-PD-1 or anti-CTLA-4 therapies.<ref name="Tian_2020" /><ref name="Kraehenbuehl_2022" /><ref name="Bosmans_2021" /><ref name="Knee_2016" />
GITR<sup>-/-</sup> mice in pancreatitis model have reduced IkBα and decreased expression of NF-kB p65 protein in pancreatic tissue, and also increased pro-apoptotic markers (e.g. Bax) and decreased anti-apoptotic markers (e.g. Bcl-2).<ref name="Bosmans_2021" /><ref>{{Cite journal | vauthors = Galuppo M, Nocentini G, Mazzon E, Ronchetti S, Esposito E, Riccardi L, Sportoletti P, Di Paola R, Bruscoli S, Riccardi C, Cuzzocrea S | title = The glucocorticoid-induced TNF receptor family-related protein (GITR) is critical to the development of acute pancreatitis in mice: Treatment of acute pancreatitis with Fc-GITR | journal = British Journal of Pharmacology | volume = 162 | issue = 5 | pages = 1186–1201 | date = March 2011 | pmid = 21091650 | pmc = 3051390 | doi = 10.1111/j.1476-5381.2010.01123.x | language = en }}</ref>
=== Atherosclerosis === Atherosclerosis is autoinflammatory disease that belongs to the group of cardiovascular diseases (CVD). In atherosclerosis progression, plaques with modified low density lipoprotein (LDL) are formed. GITR expression was detected in plaques macrophages and T cells. Moreover, soluble GITR (sGITR) was present in patient's plasma. GITR potentially might be used as a biomarker of CVD patients, as its plaque expression and levels in plasma can distinguish the CVD patients from healthy controls.<ref>{{Cite journal | vauthors = Kim WJ, Bae EM, Kang YJ, Bae HU, Hong SH, Lee JY, Park JE, Kwon BS, Suk K, Lee WH | title = Glucocorticoid-induced tumour necrosis factor receptor family related protein (GITR) mediates inflammatory activation of macrophages that can destabilize atherosclerotic plaques | journal = Immunology | volume = 119 | issue = 3 | pages = 421–429 | date = November 2006 | pmid = 17067317 | pmc = 1819571 | doi = 10.1111/j.1365-2567.2006.02453.x | language = en | issn = 0019-2805 }}</ref><ref name="Bosmans_2021" />
== Animal models ==
''Asthma model:'' GITR activation drives an infiltration of eosinophils to the lungs and induces production of cytokines. ''Model of arthritis:'' GITR activation increase numbers of Th17 cells in secondary lymphoid organs and stimulate cytokine production. ''Model of atopic dermatitis:'' GITR-GITRL pathway activation supports the production of attractants of regulatory T cells (CCL17 and CCL27) and promotes production of Th2-induced cytokines. Inhibition of GITR-GITRL pathway potentially may decrease a severity of different diseases, as asthma, arthritis or atopic dermatitis.<ref name="Bosmans_2021" /><ref>{{Cite journal | vauthors = Patel M, Xu D, Kewin P, Choo-Kang B, McSharry C, Thomson NC, Liew FY | title = Glucocorticoid-induced TNFR family-related protein (GITR) activation exacerbates murine asthma and collagen-induced arthritis | journal = European Journal of Immunology | volume = 35 | issue = 12 | pages = 3581–3590 | date = December 2005 | pmid = 16285015 | doi = 10.1002/eji.200535421 | language = en | s2cid = 11119243 | issn = 0014-2980 | doi-access = free }}</ref><ref>{{Cite journal | vauthors = Byrne AM, Goleva E, Chouiali F, Kaplan MH, Hamid QA, Leung DY | title = Induction of GITRL expression in human keratinocytes by Th2 cytokines and TNF-α: implications for atopic dermatitis | journal = Clinical and Experimental Allergy| volume = 42 | issue = 4 | pages = 550–559 | date = April 2012 | pmid = 22417213 | pmc = 3306062 | doi = 10.1111/j.1365-2222.2012.03956.x | language = en }}</ref><ref>{{Cite journal | vauthors = Byrne AM, Goleva E, Leung DY | title = Identification of Glucocorticoid-Induced TNF Receptor-Related Protein Ligand on Keratinocytes: Ligation by GITR Induces Keratinocyte Chemokine Production and Augments T-Cell Proliferation | journal = The Journal of Investigative Dermatology | volume = 129 | issue = 12 | pages = 2784–2794 | date = December 2009 | pmid = 19536139 | pmc = 8609662 | doi = 10.1038/jid.2009.163 | language = en }}</ref>
==References== {{reflist}}
==Further reading== {{refbegin | 2}} *{{cite journal | vauthors = AL G, SA M, RM H, Pitti R, Mark M, Baldwin D, Gray A, Dowd P, Brush J | title = Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR | journal = Current Biology | volume = 9 | issue = 4 | pages = 215–218 | date = Feb 1999 | pmid = 10074428 | doi = 10.1016/S0960-9822(99)80093-1 | s2cid = 110695 | doi-access = free | bibcode = 1999CBio....9..215G }} *{{cite journal | vauthors = G N, S R, A B, Spinicelli S, Delfino D, Brunetti L, Migliorati G, Riccardi C | title = Identification of three novel mRNA splice variants of GITR | journal = Cell Death and Differentiation | volume = 7 | issue = 4 | pages = 408–410 | date = Apr 2000 | pmid = 10836847 | doi = 10.1038/sj.cdd.4400670 | s2cid = 36076848 }} *{{cite journal | vauthors = RS M, MJ W, CA P, Young DA, Shevach EM, Collins M, Byrne MC | title = CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor | journal = Immunity | volume = 16 | issue = 2 | pages = 311–323 | date = Feb 2002 | pmid = 11869690 | doi = 10.1016/S1074-7613(02)00280-7 | doi-access = free }} *{{cite journal | vauthors = Ronchetti S, Nocentini G, Riccardi C, Pandolfi PP | title = Role of GITR in activation response of T lymphocytes | journal = Blood | volume = 100 | issue = 1 | pages = 350–352 | date = Jul 2002 | pmid = 12070049 | doi = 10.1182/blood-2001-12-0276 | s2cid = 5697969 | doi-access = free }} *{{cite journal | vauthors = HF C, AL G, E A, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C | title = The Secreted Protein Discovery Initiative (SPDI), a Large-Scale Effort to Identify Novel Human Secreted and Transmembrane Proteins: A Bioinformatics Assessment | journal = Genome Research | volume = 13 | issue = 10 | pages = 2265–2270 | date = Oct 2003 | pmid = 12975309 | pmc = 403697 | doi = 10.1101/gr.1293003 }} *{{cite journal | vauthors = Zhang Z, Henzel WJ | title = Signal peptide prediction based on analysis of experimentally verified cleavage sites | journal = Protein Science | volume = 13 | issue = 10 | pages = 2819–2824 | date = Oct 2004 | pmid = 15340161 | pmc = 2286551 | doi = 10.1110/ps.04682504 }} *{{cite journal | vauthors = Esparza EM, Arch RH | title = Glucocorticoid-induced TNF receptor, a costimulatory receptor on naive and activated T cells, uses TNF receptor-associated factor 2 in a novel fashion as an inhibitor of NF-kappa B activation | journal = Journal of Immunology | location = Baltimore, Md. | volume = 174 | issue = 12 | pages = 7875–7882 | date = Jun 2005 | pmid = 15944293 | doi = 10.4049/jimmunol.174.12.7875 | doi-access = free }} *{{cite journal | vauthors = J BN, C V, K TP, Deleuran M, Deleuran B | title = Glucocorticoid-induced tumour necrosis factor receptor (GITR) and its ligand (GITRL) in atopic dermatitis | journal = Acta Dermato-venereologica | volume = 86 | issue = 5 | pages = 393–398 | year = 2006 | pmid = 16955181 | doi = 10.2340/00015555-0118 | doi-access = free }} *{{cite journal | vauthors = KM B, M K, A B, Brossart P, Mayer F, Kloss M, Baessler T, Kumbier I, Peterfi A | title = Cancer immunoediting by GITR (glucocorticoid-induced TNF-related protein) ligand in humans: NK cell/tumor cell interactions | journal = FASEB Journal | volume = 21 | issue = 10 | pages = 2442–2454 | date = Aug 2007 | pmid = 17360848 | doi = 10.1096/fj.06-7724com | doi-access = free | s2cid = 6617086 }} *{{cite journal | vauthors = Lahey TP, Loisel SD, Wieland-Alter W | title = Glucocorticoid-Induced Tumor Necrosis Factor Receptor Family–Related Protein Triggering Enhances HIV-Specific CD4+ T Cell Cytokine Secretion and Protects HIV-Specific CD4+ T Cells from Apoptosis | journal = The Journal of Infectious Diseases | volume = 196 | issue = 1 | pages = 43–49 | date = Jul 2007 | pmid = 17538882 | pmc = 2872147 | doi = 10.1086/518613 }} *{{cite journal | vauthors = Coe D, Begom S, Addey C, White M, Dyson J, Chai JG | title = Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy. | journal = Cancer Immunology, Immunotherapy | volume = 59 | issue = 9 | pages = 1367–1377 | date = Sep 2010 | pmid = 20480365 | pmc = 11030908 | doi = 10.1007/s00262-010-0866-5 | s2cid = 23152321 }} {{refend}}
{{NLM content}} {{Tumor necrosis factor receptor superfamily}} {{Cytokine receptor modulators}}
Category:TNF receptor family