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Gene Review

TNFRSF18  -  tumor necrosis factor receptor superfamily...

Homo sapiens

Synonyms: AITR, Activation-inducible TNFR family receptor, CD357, GITR, GITR-D, ...
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Disease relevance of TNFRSF18


High impact information on TNFRSF18

  • Phenotypic and functional analyses demonstrated that they were antigen-specific CD4(+) Treg cells expressing CD25 and GITR molecules and possessing suppressive activity on the proliferative response of naive CD4(+) T cells to anti-CD3 antibody stimulation [6].
  • Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance [1].
  • This unique function of OX40L was not shared by two costimulatory TNF family members, GITR ligand and 4-1BB ligand [7].
  • The constitutive expression of a transfected GITR gene induced resistance to anti-CD3 mAb-induced apoptosis, whereas antisense GITR mRNA expression lead to increased sensitivity [8].
  • Thus, GITR is a new member of tumor necrosis factor/nerve growth factor receptor family involved in the regulation of T cell receptor-mediated cell death [8].

Chemical compound and disease context of TNFRSF18


Biological context of TNFRSF18


Anatomical context of TNFRSF18


Associations of TNFRSF18 with chemical compounds

  • By comparing untreated and dexamethasone-treated murine T cell hybridoma (3DO) cells by the differential display technique, we have cloned a new gene, GITR (glucocorticoid-induced tumor necrosis factor receptor family-related gene) encoding a new member of the tumor necrosis factor/nerve growth factor receptor family [8].
  • Tumor necrosis factor receptor (TNFR) family members such as glucocorticoid-induced TNFR (GITR) control T cell activation, differentiation, and effector functions [15].
  • Genetic and pharmacological inhibition of GITR-GITRL interaction reduces chronic lung injury induced by bleomycin instillation [16].
  • In contrast, in MH134 cells, PC61 induced partial tumor growth delay only when injected prior to tumor cell inoculation, and low-dose cyclophosphamide showed no effect, but GITR, particularly when administered in vitro, inhibited tumor growth [9].

Regulatory relationships of TNFRSF18

  • Direct contact between activated CD4(+) T and FLSs also induced the production of MMP-13, and neutralization of hGITR on activated CD4(+) T cells during coculture decreased the amount of MMP-13 produced by FLSs [17].

Other interactions of TNFRSF18

  • Here we report the identification of a new member, activation-inducible TNFR family member (AITR), which belongs to this subfamily, and its ligand [13].
  • OBJECTIVE: We tested the hypothesis that human glucocorticoid-induced tumor necrosis factor receptor (hGITR/TR11) expressed on the surface of activated CD4(+) T cells is responsible for up-regulating the production of matrix metalloproteinase (MMP)-13 by fibroblast-like synoviocytes (FLSs) [17].
  • GITR-induced activation of NF-kappaB is blocked by A20, an NF-kappaB-inducible protein that interacts with TRAFs and functions in a negative feedback mechanism downstream of other TNFRs [12].
  • TRAF4 functions as an intermediate of GITR-induced NF-kappaB activation [18].
  • In sum, our studies indicate that TRAF5 plays a crucial role in GITR-induced signaling pathways that augment T cell activation [15].

Analytical, diagnostic and therapeutic context of TNFRSF18


  1. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y., Sakaguchi, S. Nat. Immunol. (2002) [Pubmed]
  2. Constitutive and cytokine-induced GITR ligand expression on human retinal pigment epithelium and photoreceptors. Kim, B.J., Li, Z., Fariss, R.N., Shen, d.e. .F., Mahesh, S.P., Egwuagu, C., Yu, C.R., Nagineni, C.N., Chan, C.C., Nussenblatt, R.B. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
  3. Glucocorticoid-induced tumour necrosis factor receptor family related protein (GITR) mediates inflammatory activation of macrophages that can destabilize atherosclerotic plaques. Kim, W.J., Bae, E.M., Kang, Y.J., Bae, H.U., Hong, S.H., Lee, J.Y., Park, J.E., Kwon, B.S., Suk, K., Lee, W.H. Immunology (2006) [Pubmed]
  4. Glucocorticoid-induced Tumour Necrosis Factor Receptor (GITR) and its Ligand (GITRL) in Atopic Dermatitis. Baumgartner-Nielsen, J., Vestergaard, C., Thestrup-Pedersen, K., Deleuran, M., Deleuran, B. Acta Derm. Venereol. (2006) [Pubmed]
  5. Conversion of Alloantigen-Specific CD8+ T Cell Anergy to CD8+ T Cell Priming through In Vivo Ligation of Glucocorticoid-Induced TNF Receptor. Kim, J., Choi, W.S., Kang, H., Kim, H.J., Suh, J.H., Sakaguchi, S., Kwon, B. J. Immunol. (2006) [Pubmed]
  6. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Wang, H.Y., Lee, D.A., Peng, G., Guo, Z., Li, Y., Kiniwa, Y., Shevach, E.M., Wang, R.F. Immunity (2004) [Pubmed]
  7. OX40 ligand shuts down IL-10-producing regulatory T cells. Ito, T., Wang, Y.H., Duramad, O., Hanabuchi, S., Perng, O.A., Gilliet, M., Qin, F.X., Liu, Y.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Nocentini, G., Giunchi, L., Ronchetti, S., Krausz, L.T., Bartoli, A., Moraca, R., Migliorati, G., Riccardi, C. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  9. Distinct responses of two hepatocellular carcinoma cell lines of a similar origin to immunotherapies targeting regulatory or effector T cells. Nagayama, Y., Hase, W., Motoyoshi, Y., Saitoh, O., Sogawa, R., Nakao, K. Oncol. Rep. (2007) [Pubmed]
  10. Combined regimen of cisplatin, doxorubicin, and alpha-2b interferon in the treatment of advanced malignant pleural mesothelioma: a Phase II multicenter trial of the Italian Group on Rare Tumors (GITR) and the Italian Lung Cancer Task Force (FONICAP). Parra, H.S., Tixi, L., Latteri, F., Bretti, S., Alloisio, M., Gravina, A., Lionetto, R., Bruzzi, P., Dani, C., Rosso, R., Cosso, M., Balzarini, L., Santoro, A., Ardizzoni, A. Cancer (2001) [Pubmed]
  11. Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR. Gurney, A.L., Marsters, S.A., Huang, R.M., Pitti, R.M., Mark, D.T., Baldwin, D.T., Gray, A.M., Dowd, A.D., Brush, A.D., Heldens, A.D., Schow, A.D., Goddard, A.D., Wood, W.I., Baker, K.P., Godowski, P.J., Ashkenazi, A. Curr. Biol. (1999) [Pubmed]
  12. 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. Esparza, E.M., Arch, R.H. J. Immunol. (2005) [Pubmed]
  13. Identification of a novel activation-inducible protein of the tumor necrosis factor receptor superfamily and its ligand. 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. J. Biol. Chem. (1999) [Pubmed]
  14. Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL). Hanabuchi, S., Watanabe, N., Wang, Y.H., Wang, Y.H., Ito, T., Shaw, J., Cao, W., Qin, F.X., Liu, Y.J. Blood (2006) [Pubmed]
  15. Tumor necrosis factor receptor (TNFR)-associated factor 5 is a critical intermediate of costimulatory signaling pathways triggered by glucocorticoid-induced TNFR in T cells. Esparza, E.M., Lindsten, T., Stockhausen, J.M., Arch, R.H. J. Biol. Chem. (2006) [Pubmed]
  16. Genetic and pharmacological inhibition of GITR-GITRL interaction reduces chronic lung injury induced by bleomycin instillation. Cuzzocrea, S., Ronchetti, S., Genovese, T., Mazzon, E., Agostini, M., Di Paola, R., Esposito, E., Mui??, C., Nocentini, G., Riccardi, C. FASEB J. (2007) [Pubmed]
  17. Induction of MMP-13 expression by soluble human glucocorticoid-induced tumor necrosis factor receptor in fibroblast-like synovial cells. Kim, S.J., Shin, H.H., Park, S.Y., Lee, D.S., Lee, E.A., Cho, S.D., Cho, H.R., Miyazawa, K., Choi, H.S. Osteoarthr. Cartil. (2006) [Pubmed]
  18. TRAF4 functions as an intermediate of GITR-induced NF-kappaB activation. Esparza, E.M., Arch, R.H. Cell. Mol. Life Sci. (2004) [Pubmed]
  19. Expression of GITR ligand abrogates immunosuppressive function of ocular tissue and differentially modulates inflammatory cytokines and chemokines. Mahesh, S.P., Li, Z., Liu, B., Fariss, R.N., Nussenblatt, R.B. Eur. J. Immunol. (2006) [Pubmed]
  20. Targeting tumor-related immunosuppression for cancer immunotherapy. Frumento, G., Piazza, T., Di Carlo, E., Ferrini, S. Endocrine, metabolic & immune disorders drug targets. (2006) [Pubmed]
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