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Gene Review

Tnfrsf4  -  tumor necrosis factor receptor superfamily...

Mus musculus

Synonyms: ACT35, CD134, Ly-70, OX40 antigen, OX40L receptor, ...
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Disease relevance of Tnfrsf4


High impact information on Tnfrsf4


Chemical compound and disease context of Tnfrsf4

  • To test whether OX40/OX40L interaction plays a role in chronic intestinal inflammation, we induced chronic colitis using dextran sulfate sodium and treated the mice with a murine fusion protein (OX40-IgG) [8].

Biological context of Tnfrsf4

  • Our data demonstrate that memory T cells resisting to CD28/CD154 blockade in transplant rejection are sensitive to OX40 blockade and suggest that OX40 is a key therapeutic target in memory T cell-mediated rejection [9].
  • The affinity and kinetics of the OX40L/OX40 interactions were studied using the BIAcoreTM biosensor, which measures macromolecular interactions in real time [10].
  • Interaction of OX40 (CD134) and its ligand, OX40L, has been implicated in T cell activation and cell migration [2].
  • Engagement of OX40 enhances antigen-specific CD4(+) T cell mobilization/memory development and humoral immunity: comparison of alphaOX-40 with alphaCTLA-4 [11].
  • TCR-transgenic T cells recovered at 5 days from anti-OX40-treated mice have a unique phenotype: they remain unresponsive to Ag in vitro, but they are larger, more granular, and strongly IL-2R positive [12].

Anatomical context of Tnfrsf4

  • Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion [5].
  • The OX40 (CD134) molecule is induced primarily during T cell activation and, as we show in this study, is also expressed on CD25+CD4+ regulatory T (Treg) cells [13].
  • In vitro, we report that costimulation of naive, CD62Lhigh CD4 T cells through OX40 promotes IL-4 expression and upregulates mRNA for the chemokine receptor, blr-1, whose ligand is expressed in B follicles and attracts lymphocytes to this location [14].
  • In this study we examined the role and regulation of OX40 signals during CD4 T cell priming on dendritic cells (DCs) [15].
  • Thus, independent of IL-12, IL-18 impacts T cell immunity throughout lymphoid and nonlymphoid tissue by bridging the innate and adaptive arms of the immune system through IFN-gamma and the CD134 costimulatory pathway [16].

Associations of Tnfrsf4 with chemical compounds

  • Recent in vitro studies have established that activated B cells express OX40 ligand (L), a member of the tumor necrosis factor/nerve growth factor family of cytokines, and become stimulated to proliferate and secrete immunoglobulin (Ig) after cross-linking of OX40L by its counterreceptor OX40, which is expressed on activated T cells [17].
  • Since glucocorticoid-induced tumor necrosis factor receptor (GITR), a related TNF receptor family member, influences T reg function, we tested whether OX40 might have similar effect [18].

Regulatory relationships of Tnfrsf4


Other interactions of Tnfrsf4

  • Under the same conditions, CD8 T cells expressed 4-1BB, but no detectable OX40 [22].
  • This provides the novel concept that stimulation of CD8+ T cells by OX40 and 4-1BB ligand during priming imprints into them the capacity for secondary expansion [23].
  • Critical role of OX40 in CD28 and CD154-independent rejection [24].
  • In the present study we tested the hypothesis that the novel alternative costimulatory molecules (i.e., ICOS, 4-1BB, OX40, or CD30) may play a critical role in memory T cell activation and memory T cell-mediated rejection [9].
  • Our study revealed a key cellular mechanism of rejection and identified OX40 as a critical alternative costimulatory molecule in CD28/CD154-independent rejection [24].

Analytical, diagnostic and therapeutic context of Tnfrsf4

  • In an adoptive transfer model, CD4 T cells expressed 4-1BB and OX40 sequentially in response to immunization, with little or no overlap in the timing of their expression [22].
  • Strikingly, T reg suppression of GVHD was abrogated either by intraperitoneal injection of anti-OX40 or anti-GITR monoclonal antibodies (mAbs) immediately after transfer, or by in vitro pretreatment of T reg's with the same mAbs before transfer [18].
  • Northern blot analysis found that, as in the rat, Ox40 expression appears to be restricted to activated T cells [25].
  • Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice [26].
  • We have raised a new mAb (MRC OX86) using recombinant mouse OX40 protein and show by two-color flow cytometry that mouse OX40 is expressed on CD4 and CD8 single-positive cells [27].


  1. OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation. Salek-Ardakani, S., Song, J., Halteman, B.S., Jember, A.G., Akiba, H., Yagita, H., Croft, M. J. Exp. Med. (2003) [Pubmed]
  2. OX40 ligation on activated T cells enhances the control of Cryptococcus neoformans and reduces pulmonary eosinophilia. Humphreys, I.R., Edwards, L., Walzl, G., Rae, A.J., Dougan, G., Hill, S., Hussell, T. J. Immunol. (2003) [Pubmed]
  3. Development of allergic inflammation in a murine model of asthma is dependent on the costimulatory receptor OX40. Jember, A.G., Zuberi, R., Liu, F.T., Croft, M. J. Exp. Med. (2001) [Pubmed]
  4. Robust B cell immunity but impaired T cell proliferation in the absence of CD134 (OX40). Pippig, S.D., Peña-Rossi, C., Long, J., Godfrey, W.R., Fowell, D.J., Reiner, S.L., Birkeland, M.L., Locksley, R.M., Barclay, A.N., Killeen, N. J. Immunol. (1999) [Pubmed]
  5. Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion. Song, J., So, T., Cheng, M., Tang, X., Croft, M. Immunity (2005) [Pubmed]
  6. CD4(+)CD3(-) accessory cells costimulate primed CD4 T cells through OX40 and CD30 at sites where T cells collaborate with B cells. Kim, M.Y., Gaspal, F.M., Wiggett, H.E., McConnell, F.M., Gulbranson-Judge, A., Raykundalia, C., Walker, L.S., Goodall, M.D., Lane, P.J. Immunity (2003) [Pubmed]
  7. The costimulation-regulated duration of PKB activation controls T cell longevity. Song, J., Salek-Ardakani, S., Rogers, P.R., Cheng, M., Van Parijs, L., Croft, M. Nat. Immunol. (2004) [Pubmed]
  8. OX40/OX40L interaction induces the expression of CXCR5 and contributes to chronic colitis induced by dextran sulfate sodium in mice. Obermeier, F., Schwarz, H., Dunger, N., Strauch, U.G., Grunwald, N., Schölmerich, J., Falk, W. Eur. J. Immunol. (2003) [Pubmed]
  9. Critical, but conditional, role of OX40 in memory T cell-mediated rejection. Vu, M.D., Clarkson, M.R., Yagita, H., Turka, L.A., Sayegh, M.H., Li, X.C. J. Immunol. (2006) [Pubmed]
  10. Affinity and kinetics of the interaction between soluble trimeric OX40 ligand, a member of the tumor necrosis factor superfamily, and its receptor OX40 on activated T cells. Al-Shamkhani, A., Mallett, S., Brown, M.H., James, W., Barclay, A.N. J. Biol. Chem. (1997) [Pubmed]
  11. Engagement of OX40 enhances antigen-specific CD4(+) T cell mobilization/memory development and humoral immunity: comparison of alphaOX-40 with alphaCTLA-4. Evans, D.E., Prell, R.A., Thalhofer, C.J., Hurwitz, A.A., Weinberg, A.D. J. Immunol. (2001) [Pubmed]
  12. A signal through OX40 (CD134) allows anergic, autoreactive T cells to acquire effector cell functions. Lathrop, S.K., Huddleston, C.A., Dullforce, P.A., Montfort, M.J., Weinberg, A.D., Parker, D.C. J. Immunol. (2004) [Pubmed]
  13. Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. Takeda, I., Ine, S., Killeen, N., Ndhlovu, L.C., Murata, K., Satomi, S., Sugamura, K., Ishii, N. J. Immunol. (2004) [Pubmed]
  14. CD4 T cell cytokine differentiation: the B cell activation molecule, OX40 ligand, instructs CD4 T cells to express interleukin 4 and upregulates expression of the chemokine receptor, Blr-1. Flynn, S., Toellner, K.M., Raykundalia, C., Goodall, M., Lane, P. J. Exp. Med. (1998) [Pubmed]
  15. OX40 signals during priming on dendritic cells inhibit CD4 T cell proliferation: IL-4 switches off OX40 signals enabling rapid proliferation of Th2 effectors. Kim, M.Y., Bekiaris, V., McConnell, F.M., Gaspal, F.M., Raykundalia, C., Lane, P.J. J. Immunol. (2005) [Pubmed]
  16. IL-18 bridges innate and adaptive immunity through IFN-gamma and the CD134 pathway. Maxwell, J.R., Yadav, R., Rossi, R.J., Ruby, C.E., Weinberg, A.D., Aguila, H.L., Vella, A.T. J. Immunol. (2006) [Pubmed]
  17. The T cell-B cell interaction via OX40-OX40L is necessary for the T cell-dependent humoral immune response. Stüber, E., Strober, W. J. Exp. Med. (1996) [Pubmed]
  18. Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Valzasina, B., Guiducci, C., Dislich, H., Killeen, N., Weinberg, A.D., Colombo, M.P. Blood (2005) [Pubmed]
  19. Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses. Gramaglia, I., Weinberg, A.D., Lemon, M., Croft, M. J. Immunol. (1998) [Pubmed]
  20. Different costimulatory and growth factor requirements for CD4+ and CD8+ T cell-mediated rejection. Vu, M.D., Amanullah, F., Li, Y., Demirci, G., Sayegh, M.H., Li, X.C. J. Immunol. (2004) [Pubmed]
  21. Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand. Murata, K., Ishii, N., Takano, H., Miura, S., Ndhlovu, L.C., Nose, M., Noda, T., Sugamura, K. J. Exp. Med. (2000) [Pubmed]
  22. 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]
  23. During viral infection of the respiratory tract, CD27, 4-1BB, and OX40 collectively determine formation of CD8+ memory T cells and their capacity for secondary expansion. Hendriks, J., Xiao, Y., Rossen, J.W., van der Sluijs, K.F., Sugamura, K., Ishii, N., Borst, J. J. Immunol. (2005) [Pubmed]
  24. Critical role of OX40 in CD28 and CD154-independent rejection. Demirci, G., Amanullah, F., Kewalaramani, R., Yagita, H., Strom, T.B., Sayegh, M.H., Li, X.C. J. Immunol. (2004) [Pubmed]
  25. Cloning of mouse Ox40: a T cell activation marker that may mediate T-B cell interactions. Calderhead, D.M., Buhlmann, J.E., van den Eertwegh, A.J., Claassen, E., Noelle, R.J., Fell, H.P. J. Immunol. (1993) [Pubmed]
  26. Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice. Cuadros, C., Dominguez, A.L., Lollini, P.L., Croft, M., Mittler, R.S., Borgström, P., Lustgarten, J. Int. J. Cancer (2005) [Pubmed]
  27. OX40 is differentially expressed on activated rat and mouse T cells and is the sole receptor for the OX40 ligand. al-Shamkhani, A., Birkeland, M.L., Puklavec, M., Brown, M.H., James, W., Barclay, A.N. Eur. J. Immunol. (1996) [Pubmed]
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