TNFRSF18

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. [5][6] GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1. [7][8]

TNFRSF18
Identifiers
AliasesTNFRSF18, AITR, CD357, GITR, GITR-D, tumor necrosis factor receptor superfamily member 18, TNF receptor superfamily member 18, ENERGEN
External IDsOMIM: 603905 MGI: 894675 HomoloGene: 48270 GeneCards: TNFRSF18
Orthologs
SpeciesHumanMouse
Entrez

8784

21936

Ensembl

ENSG00000186891

ENSMUSG00000041954

UniProt

Q9Y5U5

O35714

RefSeq (mRNA)

NM_148902
NM_004195
NM_148901

NM_009400
NM_021985

RefSeq (protein)

NP_004186
NP_683699
NP_683700

NP_033426
NP_068820

Location (UCSC)Chr 1: 1.2 – 1.21 MbChr 4: 156.11 – 156.11 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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. [8] 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. [9]

GITR interacts with its ligand (GITRL) that is expressed on antigen-presenting cells (APC) and endothelial cells. [9]

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.[10]

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. [5]

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. [9][11][12][13][14]

GITR-/- 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-/- mice developed less inflammation than WT littermates. [13][15][11][14]

GITR 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. [11][16]

GITR in disease

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. [9][12][11][16]

GITR-/- 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). [11][17]

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. [11][18][19][20]

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. [21][11]

References
  1. GRCh38: Ensembl release 89: ENSG00000186891 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000041954 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Nocentini, G.; Giunchi, L.; Ronchetti, S.; Krausz, L. T.; Bartoli, A.; Moraca, R.; Migliorati, G.; Riccardi, C. (1997-06-10). "A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis". Proceedings of the National Academy of Sciences. 94 (12): 6216–6221. Bibcode:1997PNAS...94.6216N. doi:10.1073/pnas.94.12.6216. ISSN 0027-8424. PMC 21029. PMID 9177197.
  6. Nocentini, G.; Ronchetti, S.; Bartoli, A.; Spinicelli, S.; Delfino, D.; Brunetti, L.; Migliorati, G.; Riccardi, C. (April 2000). "Identification of three novel mRNA splice variants of GITR". Cell Death & Differentiation. 7 (4): 408–410. doi:10.1038/sj.cdd.4400670. ISSN 1476-5403. PMID 10836847. S2CID 36076848.
  7. Gurney, A.L.; Marsters, S.A.; Huang, A.; Pitti, R.M.; Mark, M.; Baldwin, D.T.; Gray, A.M.; Dowd, P.; Brush, J.; Heldens, S.; Schow, P. (February 1999). "Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR". Current Biology. 9 (4): 215–218. doi:10.1016/S0960-9822(99)80093-1. PMID 10074428. S2CID 110695.
  8. Kwon, Byungsuk; Yu, Kang-Yeol; Ni, Jian; Yu, Guo-Liang; Jang, Ihn-Kyung; Kim, Young-June; Xing, Lily; Liu, Ding; Wang, Shu-Xia; Kwon, Byoung S. (March 1999). "Identification of a Novel Activation-inducible Protein of the Tumor Necrosis Factor Receptor Superfamily and Its Ligand". Journal of Biological Chemistry. 274 (10): 6056–6061. doi:10.1074/jbc.274.10.6056. PMID 10037686.
  9. Tian, Jie; Zhang, Beibei; Rui, Ke; Wang, Shengjun (2020-10-09). "The Role of GITR/GITRL Interaction in Autoimmune Diseases". Frontiers in Immunology. 11: 588682. doi:10.3389/fimmu.2020.588682. ISSN 1664-3224. PMC 7581784. PMID 33163004.
  10. Park MS, Lee HM, Hahn SB, Moon SH, Kim YT, Lee CS, Jung HW, Kwon BS, Riew KD (Oct 2007). "The Association of the Activation-Inducible Tumor Necrosis Factor Receptor and Ligand with Lumbar Disc Herniation". Yonsei Med J. 48 (5): 839–46. doi:10.3349/ymj.2007.48.5.839. PMC 2628152. PMID 17963343.
  11. Bosmans, Laura A.; Shami, Annelie; Atzler, Dorothee; Weber, Christian; Gonçalves, Isabel; Lutgens, Esther (August 2021). "Glucocorticoid induced TNF receptor family-related protein (GITR) – A novel driver of atherosclerosis". Vascular Pharmacology. 139: 106884. doi:10.1016/j.vph.2021.106884. PMID 34102305. S2CID 235380691.
  12. Kraehenbuehl, Lukas; Weng, Chien-Huan; Eghbali, Shabnam; Wolchok, Jedd D.; Merghoub, Taha (January 2022). "Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways". Nature Reviews Clinical Oncology. 19 (1): 37–50. doi:10.1038/s41571-021-00552-7. ISSN 1759-4774. PMID 34580473. S2CID 237638517.
  13. Nocentini, Giuseppe; Ronchetti, Simona; Cuzzocrea, Salvatore; Riccardi, Carlo (May 2007). "GITR/GITRL: More than an effector T cell co-stimulatory system". European Journal of Immunology. 37 (5): 1165–1169. doi:10.1002/eji.200636933. PMID 17407102. S2CID 24698952.
  14. Mahmud, Shawn A; Manlove, Luke S; Schmitz, Heather M; Xing, Yan; Wang, Yanyan; Owen, David L; Schenkel, Jason M; Boomer, Jonathan S; Green, Jonathan M; Yagita, Hideo; Chi, Hongbo (May 2014). "Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells". Nature Immunology. 15 (5): 473–481. doi:10.1038/ni.2849. ISSN 1529-2908. PMC 4000541. PMID 24633226.
  15. Ronchetti, Simona; Nocentini, Giuseppe; Riccardi, Carlo; Pandolfi, Pier Paolo (2002-07-01). "Role of GITR in activation response of T lymphocytes". Blood. 100 (1): 350–352. doi:10.1182/blood-2001-12-0276. ISSN 1528-0020. PMID 12070049. S2CID 5697969.
  16. Knee, Deborah A.; Hewes, Becker; Brogdon, Jennifer L. (2016-11-01). "Rationale for anti-GITR cancer immunotherapy". European Journal of Cancer. 67: 1–10. doi:10.1016/j.ejca.2016.06.028. ISSN 0959-8049. PMID 27591414.
  17. Galuppo, M; Nocentini, G; Mazzon, E; Ronchetti, S; Esposito, E; Riccardi, L; Sportoletti, P; Di Paola, R; Bruscoli, S; Riccardi, C; Cuzzocrea, S (March 2011). "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". British Journal of Pharmacology. 162 (5): 1186–1201. doi:10.1111/j.1476-5381.2010.01123.x. PMC 3051390. PMID 21091650.
  18. Patel, Manish; Xu, Damo; Kewin, Pete; Choo-Kang, Brian; McSharry, Charles; Thomson, Neil C.; Liew, Foo Y. (December 2005). "Glucocorticoid-induced TNFR family-related protein (GITR) activation exacerbates murine asthma and collagen-induced arthritis". European Journal of Immunology. 35 (12): 3581–3590. doi:10.1002/eji.200535421. ISSN 0014-2980. PMID 16285015. S2CID 11119243.
  19. Byrne, A. M.; Goleva, E.; Chouiali, F.; Kaplan, M. H.; Hamid, Q. A.; Leung, D. Y.M. (April 2012). "Induction of GITRL expression in human keratinocytes by Th2 cytokines and TNF-α: implications for atopic dermatitis". Clinical & Experimental Allergy. 42 (4): 550–559. doi:10.1111/j.1365-2222.2012.03956.x. PMC 3306062. PMID 22417213.
  20. Byrne, Aideen M.; Goleva, Elena; Leung, Donald Y.M. (December 2009). "Identification of Glucocorticoid-Induced TNF Receptor-Related Protein Ligand on Keratinocytes: Ligation by GITR Induces Keratinocyte Chemokine Production and Augments T-Cell Proliferation". Journal of Investigative Dermatology. 129 (12): 2784–2794. doi:10.1038/jid.2009.163. PMC 8609662. PMID 19536139.
  21. Kim, Won-Jung; Bae, Eun-Mi; Kang, Yoon-Joong; Bae, Hyung-Uk; Hong, Su Hyung; Lee, Joo Y.; Park, Jeong-Euy; Kwon, Byoung S.; Suk, Kyoungho; Lee, Won-Ha (November 2006). "Glucocorticoid-induced tumour necrosis factor receptor family related protein (GITR) mediates inflammatory activation of macrophages that can destabilize atherosclerotic plaques". Immunology. 119 (3): 421–429. doi:10.1111/j.1365-2567.2006.02453.x. ISSN 0019-2805. PMC 1819571. PMID 17067317.

Further reading

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