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TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY, MEMBER 18; TNFRSF18

TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY, MEMBER 18; TNFRSF18

Alternative titles; symbolsACTIVATION-INDUCIBLE TNFR FAMILY MEMBER; AITRGLUCOCORTICOID-INDUCED TNFR-RELATED GENE; GITRHGNC Approved Gene Symbol: TNFRSF18Cytogene...

Alternative titles; symbols

  • ACTIVATION-INDUCIBLE TNFR FAMILY MEMBER; AITR
  • GLUCOCORTICOID-INDUCED TNFR-RELATED GENE; GITR

HGNC Approved Gene Symbol: TNFRSF18

Cytogenetic location: 1p36.33 Genomic coordinates (GRCh38): 1:1,203,507-1,207,900 (from NCBI)

▼ Description
Members of the tumor necrosis factor (TNF; 191160) and TNF receptor (TNFR) superfamilies, such as TNFRSF18, regulate diverse biologic functions, including cell proliferation, differentiation, and survival. For further background information on the TNF and TNFR superfamilies, see TNFRSF1A (191190).

▼ Cloning and Expression
Using differential display to identify T cell mRNAs induced by the synthetic glucocorticoid hormone dexamethasone, Nocentini et al. (1997) identified a mouse cDNA encoding a novel member of the TNFR family. They designated the corresponding gene Gitr for 'glucocorticoid-induced TNFR family-related gene.' Like other TNFRs, the predicted Gitr protein contains cysteine-rich repeats in the extracellular domain. In addition, the intracellular domain of Gitr shares significant homology with those of the mouse and human TNFRs 4-1BB (602250) and CD27 (186711).

Kwon et al. (1999) isolated cDNAs encoding the human Gitr homolog and the Gitr ligand (603898), which they designated AITR (activation-inducible TNFR family member) and AITRL, respectively. These authors reported that the predicted 234-amino acid AITR protein is a type I transmembrane protein with a signal peptide and a single transmembrane region. AITR and mouse Gitr proteins are 55% identical. Northern blot analysis revealed that the 1.25-kb AITR mRNA is expressed in lymph node, peripheral blood leukocytes, and, weakly, in spleen.

Independently, Gurney et al. (1999) identified cDNAs encoding AITR and AITRL, which they called GITR and GITRL, respectively.

▼ Gene Function
Nocentini et al. (1997) demonstrated that the Gitr gene is induced in T cells by dexamethasone as well as by other cell-activating stimuli. Gitr expression protected T cells from apoptosis induced by treatment with anti-CD3 (186790) antibodies, but not by other apoptotic agents. The authors concluded that Gitr is a new member of the TNFR family involved in the regulation of T cell receptor-mediated cell death.

Kwon et al. (1999) found that, as with other TNFR family members, when expressed in mammalian cells, AITR mediated NF-kappa-B (see 164011) activation via TRAF2 (601895). TRAF1 (601711) and TRAF3 (601896) appeared to downregulate AITR-induced NF-kappa-B activation. Expression of AITR, like that of other TNFRs, was upregulated in peripheral mononuclear cells after antigen stimulation. AITRL was constitutively expressed in an endothelial cell line, leading the authors to suggest that AITR and its ligand may be important for interactions between activated T lymphocytes and endothelial cells.

Gurney et al. (1999) found that coexpression of GITRL and GITR protected Jurkat T cells against antigen receptor-induced cell death, suggesting that GITRL and GITR may modulate T lymphocyte survival in peripheral tissues.

Ji et al. (2004) showed that a soluble form of mouse Gitrl (sGitrl) induced Gitr-dependent Nfkb (see 164011) activation and blocked in vitro suppression mediated by both resting and preactivated polyclonal and antigen-specific CD4 (186940)-positive/CD25 (IL2RA; 147730)-positive regulatory T (Treg) cells. Both sGitrl and IL2 (147680) induced proliferation of CD4-positive/CD25-positive cells, suggesting that sGitrl can break the anergic state of Treg cells. sGitrl also upregulated IL2 secretion in activated CD4-positive/CD25-negative T cells, indicating that both these sGitrl-induced signals synergize to interfere with CD4-positive/CD25-positive Treg cell suppressor activity.

Using a soluble form of Gitr, Grohmann et al. (2007) found that mouse plasmacytoid dendritic cells (pDCs) possessed Gitrl and that reverse signaling through Gitrl resulted in noncanonical Nfkb activation and onset of indoleamine 2,3-dioxygenase (IDO, or INDO; 147435)-dependent immune regulation. Administration of dexamethasone to mice activated Ido through concordant induction of Gitr in Cd4-positive T cells and Gitrl in pDCs and contributed to protection from allergic bronchopulmonary aspergillosis (see 614079). Grohmann et al. (2007) proposed that GITRL-dependent modulation of tryptophan catabolism may represent an important mechanism of action of glucocorticoids, both physiologically and therapeutically.

▼ Mapping
By radiation hybrid analysis, Gurney et al. (1999) mapped the GITR gene to 1p36.3, a region that contains the TNFRs DR3 (603366), TNFR2 (191191), CD30 (153243), OX40 (600315), and 4-1BB.

Tags: 1p36.33