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Gene Review

TNFRSF9  -  tumor necrosis factor receptor superfamily...

Homo sapiens

Synonyms: 4-1BB, 4-1BB ligand receptor, CD137, CDw137, ILA, ...
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Disease relevance of TNFRSF9


High impact information on TNFRSF9

  • Previous studies have shown that short-term administrations of agonistic monoclonal antibodies against CD137, another TNF-receptor family member, activate T cells and induce rejection of allografts and established tumors [5].
  • We reported previously that established tumors in mice receiving an agonistic mAb to the T cell costimulatory molecule 4-1BB (CD137) regress due to enhanced tumor antigen-specific cytotoxic T lymphocyte responses [6].
  • Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB [7].
  • Melanoma cells transfected to express CD83 induce antitumor immunity that can be increased by also engaging CD137 [8].
  • Compared with other activation-induced antigens, CD137 showed a superior performance based on a consistently low baseline expression and a rapid up-regulation following alloantigen stimulation [9].

Chemical compound and disease context of TNFRSF9

  • Therefore, this associated hypoglycemia was presumed to be not caused by excess glucose consumption by the tumor, not by excess secretion of IRI by the tumor, but caused by the presence of high level of ILA related to the tumor [10].

Biological context of TNFRSF9


Anatomical context of TNFRSF9


Associations of TNFRSF9 with chemical compounds

  • OX40 and 4-1BB are members of the tumor necrosis factor (TNF) family of costimulatory receptors whose signaling is important for differential immune responses mediated by CD4+ or CD8+ T cells [14].
  • Flow cytometry on propidium iodide-stained cells showed a time-dependent increase in the number of hypodiploid apoptotic cells when lymphocytes were cultured on ILA-expressing CHO cells [12].
  • The mutation of this cysteine residue exerted no effect on trimerization but increased the dissociation rate of AviTag-4-1BBL from 4-1BB [17].
  • Here, we investigated the transcriptional machinery required for T cell receptor (TCR) activation-dependent induction of 4-1BB expression in CD3-CEM cells treated with phorbol myristate acetate and ionomycin [18].
  • Thus, we tested whether the treatment with other DNA-damaging agents, such as doxorubicin, bleomycin, and gamma-irradiation, could induce 4-1BB expression [19].

Physical interactions of TNFRSF9

  • Recent studies highlight the participation of 4-1BB and its ligand 4-1BBL in a more complex network of immune cell responses and suggest that intervening in the 4-1BB costimulatory pathway might have some potential as a therapeutic approach to immune disorders [20].

Regulatory relationships of TNFRSF9

  • This indicates critical roles for IL-4 and IL-12 in regulating 4-1BB effects on TGF-beta1-mediated suppression [15].
  • The memory-type CD28(+) CTLs induced by anti-4-1BB costimulation acquired a greatly enhanced content of granzyme B, a cytolytic mediator, and enhanced cytotoxic activity as compared with CD28(-) CTLs [1].
  • Finally, agonistic anti-4-1BB antibody enhanced interferon-gamma (IFN-gamma) production and proliferation of lamina propria T cells from CD patients [2].
  • Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses [13].
  • The enhanced induction of CD30 expression by alloantigen was not common to other inducible TNFR family members because anti-CD3 plus anti-CD28 mAbs were far more effective in inducing expression of 4-1BB and OX-40 [21].

Other interactions of TNFRSF9

  • We investigated whether TGF-beta1 responses could be reversed by 4-1BB costimulation during in vitro differentiation of naive CD8+ T cells into effector CTL cells [15].
  • Taken together, our data suggest that 4-1BB/4-1BBL interactions contribute to the persistence of gut inflammation in CD [2].
  • Human 4-1BB (CD137), a member of the tumor necrosis factor receptor (TNFR) superfamily, costimulates T cell activation [11].
  • In addition, 4-1BB cross-linking with TCR signal in Jurkat cells and overexpression of 4-1BB in 293 cells were able to induce activation of the nuclear factor-kappa B (NF-kappa B) [11].
  • The heterodimer of OX40 and 4-1BB was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under nonreduced conditions and was associated with the tumor receptor-associated factor (TRAF) family proteins in a unique manner [14].

Analytical, diagnostic and therapeutic context of TNFRSF9


  1. Role of 4-1BB (CD137) in the functional activation of cord blood CD28(-)CD8(+) T cells. Kim, Y.J., Brutkiewicz, R.R., Broxmeyer, H.E. Blood (2002) [Pubmed]
  2. Functional expression of 4-1BB (CD137) in the inflammatory tissue in Crohn's disease. Maerten, P., Geboes, K., De Hertogh, G., Shen, C., Cadot, P., Bullens, D.M., Van Assche, G., Penninckx, F., Rutgeerts, P., Ceuppens, J.L. Clin. Immunol. (2004) [Pubmed]
  3. Analysis of costimulatory molecules OX40/4-1BB (CD134/CD137) detection on chosen mononuclear cells in children and adolescents with Graves' disease during methimazole therapy. Bossowski, A., Stasiak-Barmuta, A., Urban, M., Bossowska, A. J. Pediatr. Endocrinol. Metab. (2005) [Pubmed]
  4. Biological activities of reverse signal transduction through CD137 ligand. Schwarz, H. J. Leukoc. Biol. (2005) [Pubmed]
  5. Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Sun, Y., Chen, H.M., Subudhi, S.K., Chen, J., Koka, R., Chen, L., Fu, Y.X. Nat. Med. (2002) [Pubmed]
  6. Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. Wilcox, R.A., Flies, D.B., Zhu, G., Johnson, A.J., Tamada, K., Chapoval, A.I., Strome, S.E., Pease, L.R., Chen, L. J. Clin. Invest. (2002) [Pubmed]
  7. Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB. Maus, M.V., Thomas, A.K., Leonard, D.G., Allman, D., Addya, K., Schlienger, K., Riley, J.L., June, C.H. Nat. Biotechnol. (2002) [Pubmed]
  8. Melanoma cells transfected to express CD83 induce antitumor immunity that can be increased by also engaging CD137. Yang, S., Yang, Y., Raycraft, J., Zhang, H., Kanan, S., Guo, Y., Ronai, Z., Hellstrom, I., Hellstrom, K.E. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  9. Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. Wehler, T.C., Nonn, M., Brandt, B., Britten, C.M., Gr??ne, M., Todorova, M., Link, I., Khan, S.A., Meyer, R.G., Huber, C., Hartwig, U.F., Herr, W. Blood (2007) [Pubmed]
  10. Retroperitoneal hemangiopericytoma associated with hypoglycemia: report of a case. Yasuda, Y., Kasahara, K., Tenmoku, S., Yabe, C., Miyata, M., Morioka, Y., Sakamoto, Y., Kuzuya, T., Takeda, K., Atsumi, T., Shimizu, H., Matsumoto, S. The Japanese journal of surgery. (1979) [Pubmed]
  11. Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B. Jang, I.K., Lee, Z.H., Kim, Y.J., Kim, S.H., Kwon, B.S. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  12. ILA, a member of the human nerve growth factor/tumor necrosis factor receptor family, regulates T-lymphocyte proliferation and survival. Schwarz, H., Blanco, F.J., von Kempis, J., Valbracht, J., Lotz, M. Blood (1996) [Pubmed]
  13. Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses. Kim, Y.J., Kim, S.H., Mantel, P., Kwon, B.S. Eur. J. Immunol. (1998) [Pubmed]
  14. The expression and the regulatory role of OX40 and 4-1BB heterodimer in activated human T cells. Ma, B.Y., Mikolajczak, S.A., Danesh, A., Hosiawa, K.A., Cameron, C.M., Takaori-Kondo, A., Uchiyama, T., Kelvin, D.J., Ochi, A. Blood (2005) [Pubmed]
  15. Modulation of cord blood CD8+ T-cell effector differentiation by TGF-beta1 and 4-1BB costimulation. Kim, Y.J., Stringfield, T.M., Chen, Y., Broxmeyer, H.E. Blood (2005) [Pubmed]
  16. Constitutive expression of functional 4-1BB (CD137) ligand on carcinoma cells. Salih, H.R., Kosowski, S.G., Haluska, V.F., Starling, G.C., Loo, D.T., Lee, F., Aruffo, A.A., Trail, P.A., Kiener, P.A. J. Immunol. (2000) [Pubmed]
  17. Production of recombinant human trimeric CD137L (4-1BBL). Cross-linking is essential to its T cell co-stimulation activity. Rabu, C., Quéméner, A., Jacques, Y., Echasserieau, K., Vusio, P., Lang, F. J. Biol. Chem. (2005) [Pubmed]
  18. NF-kappaB and AP-1 regulate activation-dependent CD137 (4-1BB) expression in T cells. Kim, J.O., Kim, H.W., Baek, K.M., Kang, C.Y. FEBS Lett. (2003) [Pubmed]
  19. Induction of 4-1BB (CD137) expression by DNA damaging agents in human T lymphocytes. Kim, K.M., Kim, H.W., Kim, J.O., Baek, K.M., Kim, J.G., Kang, C.Y. Immunology (2002) [Pubmed]
  20. New insights into the role of 4-1BB in immune responses: beyond CD8+ T cells. Kwon, B., Lee, H.W., Kwon, B.S. Trends Immunol. (2002) [Pubmed]
  21. CD30 expression identifies the predominant proliferating T lymphocyte population in human alloimmune responses. Chan, K.W., Hopke, C.D., Krams, S.M., Martinez, O.M. J. Immunol. (2002) [Pubmed]
  22. Expression of CD137 and its ligand in human neurons, astrocytes, and microglia: modulation by FGF-2. Reali, C., Curto, M., Sogos, V., Scintu, F., Pauly, S., Schwarz, H., Gremo, F. J. Neurosci. Res. (2003) [Pubmed]
  23. CD137, a member of the tumor necrosis factor receptor family, is located on chromosome 1p36, in a cluster of related genes, and colocalizes with several malignancies. Schwarz, H., Arden, K., Lotz, M. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  24. Expression of co-stimulator 4-1BB molecule in hepatocellular carcinoma and adjacent non-tumor liver tissue, and its possible role in tumor immunity. Wan, Y.L., Zheng, S.S., Zhao, Z.C., Li, M.W., Jia, C.K., Zhang, H. World J. Gastroenterol. (2004) [Pubmed]
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