Alternative titles; symbols
HGNC Approved Gene Symbol: TNFSF18
Cytogenetic location: 1q25.1 Genomic coordinates (GRCh38): 1:173,039,202-173,050,941 (from NCBI)
Members of the tumor necrosis factor (TNF; 191160) and TNF receptor (TNFR) superfamilies, such as TNFSF18, regulate diverse biologic functions, including cell proliferation, differentiation, and survival. For further background information on the TNF and TNFR superfamilies, see TNFRSF1A (191190).
Nocentini et al. (1997) identified Gitr (glucocorticoid-induced TNFR family-related gene; 603905), a mouse TNFR that inhibits T cell receptor-induced apoptosis. Kwon et al. (1999) isolated the human Gitr homolog, which they designated AITR. By screening a panel of epitope-tagged candidate TNF ligand proteins for binding to a recombinant AITR protein, these authors identified the AITR ligand, AITRL or TL6. Northern blot analysis revealed that TL6 is expressed as a 2.4-kb mRNA in pancreas. Using RT-PCR, these authors found that TL6 was expressed constitutively in an endothelial cell line, and that its expression was upregulated after stimulation by lipopolysaccharide. They suggested that AITR and AITRL are important for interactions between activated T lymphocytes and endothelial cells.
Independently, Gurney et al. (1999) isolated cDNAs encoding human GITR and the GITR ligand (GITRL). They reported that the predicted GITRL protein contains 177 amino acids and has a type II transmembrane topology characteristic of the TNF family.
Gurney et al. (1999) found that coexpression of GITR and GITRL in mammalian cells activated the antiapoptotic transcription factor NF-kappa-B (see 164011), and coexpression in Jurkat T cells inhibited antigen receptor-induced cell death. Gurney et al. (1999) suggested 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.
By radiation hybrid analysis, Gurney et al. (1999) mapped the GITRL gene to 1q23.
Grohmann, U., Volpi, C., Fallarino, F., Bozza, S., Bianchi, R., Vacca, C., Orabona, C., Belladonna, M. L., Ayroldi, E., Nocentini, G., Boon, L., Bistoni, F., Fioretti, M. C., Romani, L., Riccardi, C., Puccetti, P. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nature Med. 13: 579-586, 2007. [PubMed: 17417651] [Full Text: https://doi.org/10.1038/nm1563]
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., Goddard, A. D., Wood, W. I., Baker, K. P., Godowski, P. J., Ashkenazi, A. Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR. Curr. Biol. 9: 215-218, 1999. [PubMed: 10074428] [Full Text: https://doi.org/10.1016/s0960-9822(99)80093-1]
Ji, H., Liao, G., Faubion, W. A., Abadia-Molina, A. C., Cozzo, C., Laroux, F. S., Caton, A., Terhorst, C. Cutting edge: the natural ligand for glucocorticoid-induced TNF receptor-related protein abrogates regulatory T cell suppression. J. Immun. 172: 5823-5827, 2004. [PubMed: 15128759] [Full Text: https://doi.org/10.4049/jimmunol.172.10.5823]
Kwon, B., Yu, K.-Y., Ni, J., Yu, G.-L., Jang, I.-K., Kim, Y.-J., Xing, L., Liu, D., Wang, S.-X., Kwon, B. S. Identification of a novel activation-inducible protein of the tumor necrosis factor receptor superfamily and its ligand. J. Biol. Chem. 274: 6056-6061, 1999. [PubMed: 10037686] [Full Text: https://doi.org/10.1074/jbc.274.10.6056]
Nocentini, G., Giunchi, L., Ronchetti, S., Krausz, L. T., Bartoli, A., Moraca, R., Migliorati, G., Riccardi, C. A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Proc. Nat. Acad. Sci. 94: 6216-6221, 1997. [PubMed: 9177197] [Full Text: https://doi.org/10.1073/pnas.94.12.6216]