The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

Tnfrsf9  -  tumor necrosis factor receptor superfamily...

Mus musculus

Synonyms: 4-1BB, 4-1BB ligand receptor, A930040I11Rik, AA408498, AI325004, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of Tnfrsf9


High impact information on Tnfrsf9

  • Monoclonal antibodies against the T-cell activation molecule 4-1BB have been effective in the treatment of established mouse tumors [6].
  • Expression of 4-1BB is restricted to primed CD4+ and CD8+ T cells, and 4-1BB signaling either by binding to 4-1BBL or by antibody ligation delivers a dual mitogenic signal for T-cell activation and growth [7].
  • The 4-1BB glycoprotein is a member of the tumor necrosis factor receptor superfamily and binds to a high-affinity ligand (4-1BBL) expressed on several antigen-presenting cells such as macrophages and activated B cells [7].
  • Here we show that anti-mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells [8].
  • The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation [9].

Chemical compound and disease context of Tnfrsf9

  • In this study, we demonstrate that several poorly immunogenic tumors, including C3 tumor, TC-1 lung carcinoma, and B16-F10 melanoma, once established as solid tumors or metastases, are refractory to treatment by anti-4-1BB mAb [10].

Biological context of Tnfrsf9


Anatomical context of Tnfrsf9


Associations of Tnfrsf9 with chemical compounds

  • These data are the first to suggest a stimulatory role for endogenous 4-1BB-4-1BBL interactions during a humoral immune response to a pathogen and further underscore significant differences in costimulation requirements for an in vivo protein- versus polysaccharide-specific Ig isotype response to an extracellular bacterium [4].
  • The interaction between extracellular matrix proteins and 4-1BB was completely blocked by the anionic carbohydrate polymer fucoidan and was partially blocked by the anionic carbohydrate polymer dextran sulfate and the glycosaminoglycan heparin sulfate but was unaffected by desulfated heparin [17].
  • Optimal induction of 4-1BB mRNA in T cells required both PMA and ionomycin stimulation, indicating that protein kinase C activation and increases in intracellular Ca2+ were required for its expression [18].
  • 4-1BB extracellular domain contains four potential C6 (CXn C XX C XX CXn C Xn C) motifs, of which the first motif is partial and the third is distinct from those of nerve growth factor receptor or TNF receptor 1 [19].
  • 4-1BB was categorized as an early activation gene since the protein synthesis inhibitor, cycloheximide, blocked the induction of 4-1BB mRNA [18].

Physical interactions of Tnfrsf9

  • 4-1BBL binds to 4-1BB (CD137) on activated CD4 and CD8 T cells and in conjunction with strong signals through the TCR provides a CD28-independent costimulatory signal leading to high level IL-2 production by primary resting T cells [20].

Regulatory relationships of Tnfrsf9


Other interactions of Tnfrsf9

  • Under the same conditions, CD8 T cells expressed 4-1BB, but no detectable OX40 [23].
  • Introduction: 4-1BB is an inducible T-cell costimulatory molecule and a member of the TNF receptor family [12].
  • Regulation of 4-1BB expression by cell-cell interactions and the cytokines, interleukin-2 and interleukin-4 [14].
  • T cells activated with soluble anti-CD3 (anti-CD3s) in the presence of IL-2, IL-4, or accessory cells, did not express higher levels of 4-1BB on their cell surface [14].
  • These data suggest that initial events crucial for efficient T cell activation, such as signals delivered through the T cell receptor/CD3 complex and the CD28 molecule, are instrumental in regulating subsequent 4-1BB expression [14].

Analytical, diagnostic and therapeutic context of Tnfrsf9


  1. 4-1BB costimulation is required for protective anti-viral immunity after peptide vaccination. Tan, J.T., Whitmire, J.K., Murali-Krishna, K., Ahmed, R., Altman, J.D., Mittler, R.S., Sette, A., Pearson, T.C., Larsen, C.P. J. Immunol. (2000) [Pubmed]
  2. Infection-induced up-regulation of the costimulatory molecule 4-1BB in osteoblastic cells and its inhibitory effect on M-CSF/RANKL-induced in vitro osteoclastogenesis. Saito, K., Ohara, N., Hotokezaka, H., Fukumoto, S., Yuasa, K., Naito, M., Fujiwara, T., Nakayama, K. J. Biol. Chem. (2004) [Pubmed]
  3. Blocking 4-1BB/4-1BB ligand interactions prevents herpetic stromal keratitis. Seo, S.K., Park, H.Y., Choi, J.H., Kim, W.Y., Kim, Y.H., Jung, H.W., Kwon, B., Lee, H.W., Kwon, B.S. J. Immunol. (2003) [Pubmed]
  4. 4-1BB (CD137) differentially regulates murine in vivo protein- and polysaccharide-specific immunoglobulin isotype responses to Streptococcus pneumoniae. Wu, Z.Q., Khan, A.Q., Shen, Y., Wolcott, K.M., Dawicki, W., Watts, T.H., Mittler, R.S., Snapper, C.M. Infect. Immun. (2003) [Pubmed]
  5. Genetic and functional association of the immune signaling molecule 4-1BB (CD137/TNFRSF9) with type 1 diabetes. Cannons, J.L., Chamberlain, G., Howson, J., Smink, L.J., Todd, J.A., Peterson, L.B., Wicker, L.S., Watts, T.H. J. Autoimmun. (2005) [Pubmed]
  6. Gene therapy for cancer using single-chain Fv fragments specific for 4-1BB. Ye, Z., Hellström, I., Hayden-Ledbetter, M., Dahlin, A., Ledbetter, J.A., Hellström, K.E. Nat. Med. (2002) [Pubmed]
  7. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Melero, I., Shuford, W.W., Newby, S.A., Aruffo, A., Ledbetter, J.A., Hellström, K.E., Mittler, R.S., Chen, L. Nat. Med. (1997) [Pubmed]
  8. Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy. Mittler, R.S., Bailey, T.S., Klussman, K., Trailsmith, M.D., Hoffmann, M.K. J. Exp. Med. (1999) [Pubmed]
  9. 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. Shuford, W.W., Klussman, K., Tritchler, D.D., Loo, D.T., Chalupny, J., Siadak, A.W., Brown, T.J., Emswiler, J., Raecho, H., Larsen, C.P., Pearson, T.C., Ledbetter, J.A., Aruffo, A., Mittler, R.S. J. Exp. Med. (1997) [Pubmed]
  10. 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]
  11. 4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy. Cannons, J.L., Lau, P., Ghumman, B., DeBenedette, M.A., Yagita, H., Okumura, K., Watts, T.H. J. Immunol. (2001) [Pubmed]
  12. Enhanced Osteoclastogenesis in 4-1BB-Deficient Mice Caused by Reduced Interleukin-10. Shin, H.H., Lee, J.E., Lee, E.A., Kwon, B.S., Choi, H.S. J. Bone Miner. Res. (2006) [Pubmed]
  13. 4-1BB enhances CD8+ T cell expansion by regulating cell cycle progression through changes in expression of cyclins D and E and cyclin-dependent kinase inhibitor p27kip1. Lee, H.W., Nam, K.O., Park, S.J., Kwon, B.S. Eur. J. Immunol. (2003) [Pubmed]
  14. Regulation of 4-1BB expression by cell-cell interactions and the cytokines, interleukin-2 and interleukin-4. Pollok, K.E., Kim, S.H., Kwon, B.S. Eur. J. Immunol. (1995) [Pubmed]
  15. MIP-1alpha and MIP-1beta differentially mediate mucosal and systemic adaptive immunity. Lillard, J.W., Singh, U.P., Boyaka, P.N., Singh, S., Taub, D.D., McGhee, J.R. Blood (2003) [Pubmed]
  16. Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. Futagawa, T., Akiba, H., Kodama, T., Takeda, K., Hosoda, Y., Yagita, H., Okumura, K. Int. Immunol. (2002) [Pubmed]
  17. T-cell activation molecule 4-1BB binds to extracellular matrix proteins. Chalupny, N.J., Peach, R., Hollenbaugh, D., Ledbetter, J.A., Farr, A.G., Aruffo, A. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  18. Inducible T cell antigen 4-1BB. Analysis of expression and function. Pollok, K.E., Kim, Y.J., Zhou, Z., Hurtado, J., Kim, K.K., Pickard, R.T., Kwon, B.S. J. Immunol. (1993) [Pubmed]
  19. Genomic organization and chromosomal localization of the T-cell antigen 4-1BB. Kwon, B.S., Kozak, C.A., Kim, K.K., Pickard, R.T. J. Immunol. (1994) [Pubmed]
  20. Analysis of 4-1BB ligand (4-1BBL)-deficient mice and of mice lacking both 4-1BBL and CD28 reveals a role for 4-1BBL in skin allograft rejection and in the cytotoxic T cell response to influenza virus. DeBenedette, M.A., Wen, T., Bachmann, M.F., Ohashi, P.S., Barber, B.H., Stocking, K.L., Peschon, J.J., Watts, T.H. J. Immunol. (1999) [Pubmed]
  21. Amplification of tumor immunity by gene transfer of the co-stimulatory 4-1BB ligand: synergy with the CD28 co-stimulatory pathway. Melero, I., Bach, N., Hellström, K.E., Aruffo, A., Mittler, R.S., Chen, L. Eur. J. Immunol. (1998) [Pubmed]
  22. Role of TNF receptor-associated factor 2 and p38 mitogen-activated protein kinase activation during 4-1BB-dependent immune response. Cannons, J.L., Choi, Y., Watts, T.H. J. Immunol. (2000) [Pubmed]
  23. 4-1BB and OX40 act independently to facilitate robust CD8 and CD4 recall responses. Dawicki, W., Bertram, E.M., Sharpe, A.H., Watts, T.H. J. Immunol. (2004) [Pubmed]
  24. Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. Goodwin, R.G., Din, W.S., Davis-Smith, T., Anderson, D.M., Gimpel, S.D., Sato, T.A., Maliszewski, C.R., Brannan, C.I., Copeland, N.G., Jenkins, N.A. Eur. J. Immunol. (1993) [Pubmed]
  25. Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation. Kim, J.A., Averbook, B.J., Chambers, K., Rothchild, K., Kjaergaard, J., Papay, R., Shu, S. Cancer Res. (2001) [Pubmed]
WikiGenes - Universities