International Journal of Hematology

, Volume 83, Issue 1, pp 17–22 | Cite as

Roles of OX40 in the Pathogenesis and the Control of Diseases

  • Toshiyuki Hori


OX40 belongs to the tumor necrosis factor receptor superfamily, and its expression is restricted to activated T-cells. Ligation of OX40 during T-cell-dendritic cell interaction is crucial for clonal expansion of antigen-specific T-cells and generation of T-cell memory. The ligand of OX40 (OX40L) is expressed not only on dendritic cells but also on other cell types, such as B-cells, vascular endothelial cells, natural killer cells, and mast cells. The pathophysiological relevance of this broad distribution needs further investigation. In particular, OX40L on vascular endothelial cells may play a role in inflammatory vasculitis as well as in atherosclerotic change. Recent studies with animal models have indicated the critical involvement of OX40 in the pathogenesis of a variety of immunologic abnormalities of inflammatory, autoimmune, infectious, allergic, and allotransplantation-Related diseases. Blockade of OX40-OX40L interaction has been shown to prevent, cure, or ameliorate these diseases. In contrast, activation of OX40 is known to break an existing state of tolerance in malignancies, leading to a reactivation of antitumor immunity. These findings clearly suggest that the OX40/OX40L system is one of the most promising targets of immune intervention for treatment of these diseases.

Key words

OX40 OX40L T-cell Costimulation Immune intervention 


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  1. 1.
    Takasawa N, Ishii N, Higashimura N, et al. Expression of gp34 (OX40 ligand) and OX40 on human T cell clones. Jpn J Cancer Res. 2001;92:377–382.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Baum PR, Gayle RB 3rd, Ramsdell F, et al. Molecular characterization of murine and human OX40/OX40 ligand systems: identification of a human OX40 ligand as the HTLV-1-regulated protein gp34. EMBO J. 1994;13:3992–4001.CrossRefGoogle Scholar
  3. 3.
    Walker LS, Gulbranson-Judge A, Flynn S, et al. Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5-positive CD4 cells and germinal centers. J Exp Med. 1999;190:1115–1122.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ohshima Y, Tanaka Y, Tozawa H, Takahashi Y, Maliszewski C, Delespesse G. Expression and function of OX40 ligand on human dendritic cells. J Immunol. 1997;159:3838–3848.PubMedGoogle Scholar
  5. 5.
    Ito T, Amakawa R, Inaba M, et al. Plasmacytoid dendritic cells regulate Th cell responses through OX40 ligand and type I IFNs. J Immunol. 2004;172:4253–4259.CrossRefPubMedGoogle Scholar
  6. 6.
    Stuber E, Neurath M, Calderhead D, Fell HP, Strober W. Cross- linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells. Immunity. 1995;2:507–521.CrossRefPubMedGoogle Scholar
  7. 7.
    Miura S, Ohtani K, Numata N, et al. Molecular cloning and characterization of a novel glycoprotein, gp34, that is specifically induced by the human T-cell leukemia virus type I transactivator p40tax. Mol Cell Biol. 1991;11:1313–1325.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Imura A, Hori T, Imada K, et al. The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothe- lial cells. J Exp Med. 1996;183:2185–2195.CrossRefPubMedGoogle Scholar
  9. 9.
    Kashiwakura J, Yokoi H, Saito H, Okayama Y. T cell proliferation by direct cross-talk between OX40 ligand on human mast cells and OX40 on human T cells: comparison of gene expression profiles between human tonsillar and lung-cultured mast cells. J Immunol. 2004;173:5247–5257.CrossRefPubMedGoogle Scholar
  10. 10.
    Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL. Cross-talk between activated human NK cells and CD4+ T cells via OX40-OX40 ligand interactions. J Immunol. 2004;173:3716–3724.CrossRefPubMedGoogle Scholar
  11. 11.
    Nohara C, Akiba H, Nakajima A, et al. Amelioration of experimental autoimmune encephalomyelitis with anti-OX40 ligand monoclonal antibody: a critical role for OX40 ligand in migration, but not development, of pathogenic T cells. J Immunol. 2001;166: 2108–2115.CrossRefPubMedGoogle Scholar
  12. 12.
    Kunitomi A, Hori T, Imura A, Uchiyama T. Vascular endothelial cells provide T cells with costimulatory signals via the OX40/gp34 system. J Leukoc Biol. 2000;68:111–118.PubMedGoogle Scholar
  13. 13.
    Kotani A, Hori T, Matsumura Y, Uchiyama T. Signaling of gp34 (OX40 ligand) induces vascular endothelial cells to produce a CC chemokine RANTES/CCL5. Immunol Lett. 2002;84:1–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Wang X, Ria M, Kelmenson PM, et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nat Genet. 2005;37:365–372.CrossRefPubMedGoogle Scholar
  15. 15.
    Chung JY, Park YC, Ye H, Wu H. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci. 2002;115:679–688.PubMedGoogle Scholar
  16. 16.
    Kawamata S, Hori T, Imura A, Takaori-Kondo A, Uchiyama T. Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2- and TRAF5- mediated NF-κB activation. J Biol Chem. 1998;273:5808–5814.CrossRefPubMedGoogle Scholar
  17. 17.
    Arch RH, Thompson CB. 4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kB. Mol Cell Biol. 1998;18:558–565.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rogers PR, Song J, Gramaglia I, Killeen N, Croft M. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4T cells. Immunity. 2001;15:445–455.CrossRefPubMedGoogle Scholar
  19. 19.
    Song J, Salek-Ardakani S, Rogers PR, Cheng M, Van Parijs L, Croft M. The costimulation-regulated duration of PKB activation controls T cell longevity. Nat Immunol. 2004;5:150–158.CrossRefPubMedGoogle Scholar
  20. 20.
    Prell RA, Evans DE, Thalhofer C, Shi T, Funatake C, Weinberg AD. OX40-mediated memory T cell generation is TNF receptor-associated factor 2 dependent. J Immunol. 2003;171:5997–6005.CrossRefPubMedGoogle Scholar
  21. 21.
    Song J, So T, Cheng M, Tang X, Croft M. Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion. Immunity. 2005;22:621–631.CrossRefPubMedGoogle Scholar
  22. 22.
    Mestas J, Crampton SP, Hori T, Hughes CC. Endothelial cell co- stimulation through OX40 augments and prolongs T cell cytokine synthesis by stabilization of cytokine mRNA. Int Immunol. 2005; 17:737–747.CrossRefPubMedGoogle Scholar
  23. 23.
    Chen AI, McAdam AJ, Buhlmann JE, et al. Ox40-ligand has a critical costimulatory role in dendritic cell:T cell interactions. Immunity. 1999;11:689–698.CrossRefPubMedGoogle Scholar
  24. 24.
    Kopf M, Ruedl C, Schmitz N, et al. OX40-deficient mice are defective in Th cell proliferation but are competent in generating B cell and CTL responses after virus infection. Immunity. 1999;11:699–708.CrossRefPubMedGoogle Scholar
  25. 25.
    Murata K, Ishii N, Takano H, et al. Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand. J Exp Med. 2000;191:365–374.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kim MY, Gaspal FM, Wiggett HE, et al. CD4+CD3- accessory cells costimulate primed CD4 T cells through OX40 and CD30 at sites where T cells collaborate with B cells. Immunity. 2003;18:643–654.CrossRefPubMedGoogle Scholar
  27. 27.
    Arestides RS, He H, Westlake RM, et al. Costimulatory molecule OX40L is critical for both Th1 and Th2 responses in allergic inflammation. Eur J Immunol. 2002;32:2874–2880.CrossRefPubMedGoogle Scholar
  28. 28.
    Weinberg AD, Wegmann KW, Funatake C, Whitham RH. Blocking OX-40/OX-40 ligand interaction in vitro and in vivo leads to decreased T cell function and amelioration of experimental allergic encephalomyelitis. J Immunol. 1999;162:1818–1826.PubMedGoogle Scholar
  29. 29.
    Higgins LM, McDonald SA, Whittle N, Crockett N, Shields JG, MacDonald TT. Regulation of T cell activation in vitro and in vivo by targeting the OX40-OX40 ligand interaction: amelioration of ongoing inflammatory bowel disease with an OX40-IgG fusion protein, but not with an OX40 ligand-IgG fusion protein. J Immunol. 1999;162:486–493.PubMedGoogle Scholar
  30. 30.
    Yoshioka T, Nakajima A, Akiba H, et al. Contribution of OX40/ OX40 ligand interaction to the pathogenesis of rheumatoid arthritis. Eur J Immunol. 2000;30:2815–2823.CrossRefPubMedGoogle Scholar
  31. 31.
    Giacomelli R, Passacantando A, Perricone R, et al. T lymphocytes in the synovial fluid of patients with active rheumatoid arthritis display CD134-OX40 surface antigen. Clin Exp Rheumatol. 2001;19: 317–320.PubMedGoogle Scholar
  32. 32.
    Lathrop SK, Huddleston CA, Dullforce PA, Montfort MJ, Weinberg AD, Parker DC. A signal through OX40 (CD134) allows anergic, autoreactive T cells to acquire effector cell functions. J Immunol. 2004;172:6735–6743.CrossRefPubMedGoogle Scholar
  33. 33.
    Murata K, Nose M, Ndhlovu LC, Sato T, Sugamura K, Ishii N. Constitutive OX40/OX40 ligand interaction induces autoimmune-like diseases. J Immunol. 2002;169:4628–4636.CrossRefPubMedGoogle Scholar
  34. 34.
    Humphreys IR, Edwards L, Walzl G, et al. OX40 ligation on activated T cells enhances the control of Cryptococcus neoformans and reduces pulmonary eosinophilia. J Immunol. 2003;170:6125–6132.CrossRefPubMedGoogle Scholar
  35. 35.
    Zubairi S, Sanos SL, Hill S, Kaye PM. Immunotherapy with OX40L-Fc or anti-CTLA-4 enhances local tissue responses and killing of Leishmania donovani. Eur J Immunol. 2004;34:1433–1440.CrossRefPubMedGoogle Scholar
  36. 36.
    Akiba H, Miyahira Y, Atsuta M, et al. Critical contribution of OX40 ligand to T helper cell type 2 differentiation in experimental leishmaniasis. J Exp Med. 2000;191:375–380.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ishii N, Ndhlovu LC, Murata K, Sato T, Kamanaka M, Sugamura K. OX40 (CD134) and OX40 ligand interaction plays an adjuvant role during in vivo Th2 responses. Eur J Immunol. 2003;33:2372–2381.CrossRefPubMedGoogle Scholar
  38. 38.
    Humphreys IR, Walzl G, Edwards L, Rae A, Hill S, Hussell T. A critical role for OX40 in T cell-mediated immunopathology during lung viral infection. J Exp Med. 2003;198:1237–1242.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Jember AG, Zuberi R, Liu FT, Croft M. Development of allergic inflammation in a murine model of asthma is dependent on the costimulatory receptor OX40. J Exp Med. 2001;193:387–392.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hoshino A, Tanaka Y, Akiba H, et al. Critical role for OX40 ligand in the development of pathogenic Th2 cells in a murine model of asthma. Eur J Immunol. 2003;33:861–869.CrossRefPubMedGoogle Scholar
  41. 41.
    Ying S, O’Connor B, Ratoff J, et al. Thymic stromal lymphopoi- etin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol. 2005;174:8183–8190.CrossRefPubMedGoogle Scholar
  42. 42.
    Al-Shami A, Spolski R, Kelly J, Keane-Myers A, Leonard WJ. A role for TSLP in the development of inflammation in an asthma model. J Exp Med. 2005;202:829–839.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zhou B, Comeau MR, de Smedt T, et al. Thymic stromal lym- phopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol. 2005;6:1047–1053.CrossRefPubMedGoogle Scholar
  44. 44.
    Ito T, Wang Y-H, Duramad O, et al. TSLP-activated dendritic cells induce inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med. 2005;202:1213–1223.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Stuber E, Von Freier A, Marinescu D, Folsch UR. Involvement of OX40-OX40L interactions in the intestinal manifestations of the murine acute graft-versus-host disease. Gastroenterology. 1998;115: 1205–1215.CrossRefPubMedGoogle Scholar
  46. 46.
    Tsukada N, Akiba H, Kobata T, Aizawa Y, Yagita H, Okumura K. Blockade of CD134 (OX40)-CD134L interaction ameliorates lethal acute graft-versus-host disease in a murine model of allo-geneic bone marrow transplantation. Blood. 2000;95:2434–2439.PubMedGoogle Scholar
  47. 47.
    Blazar BR, Sharpe AH, Chen AI, et al. Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients. Blood. 2003;101: 3741–3748.CrossRefPubMedGoogle Scholar
  48. 48.
    Tittle TV, Weinberg AD, Steinkeler CN, Maziarz RT. Expression of the T-cell activation antigen, OX-40, identifies alloreactive T cells in acute graft-versus-host disease. Blood. 1997;89:4652–4658.PubMedGoogle Scholar
  49. 49.
    Kotani A, Ishikawa T, Matsumura Y, et al. Correlation of peripheral blood OX40+(CD134+) T cells with chronic graft-versus-host disease in patients who underwent allogeneic hematopoietic stem cell transplantation. Blood. 2001;98:3162–3164.CrossRefPubMedGoogle Scholar
  50. 50.
    Curry AJ, Chikwe J, Smith XG, et al. OX40 (CD134) blockade inhibits the co-stimulatory cascade and promotes heart allograft survival. Transplantation. 2004;78:807–814.CrossRefPubMedGoogle Scholar
  51. 51.
    Demirci G, Amanullah F, Kewalaramani R, et al. Critical role of OX40 in CD28 and CD154-independent rejection. J Immunol. 2004;172:1691–1698.CrossRefPubMedGoogle Scholar
  52. 52.
    Briones J, Timmerman J, Levy R. In vivo antitumor effect of CD40L-transduced tumor cells as a vaccine for B-cell lymphoma. Cancer Res. 2002;62:3195–3199.PubMedGoogle Scholar
  53. 53.
    Cayeux S, Beck C, Aicher A, Dorken B, Blankenstein T. Tumor cells cotransfected with interleukin-7 and B7.1 genes induce CD25 and CD28 on tumor-infiltrating T lymphocytes and are strong vaccines. Eur J Immunol. 1995;25:2325–2331.CrossRefPubMedGoogle Scholar
  54. 54.
    Bansal-Pakala P, Jember AG, Croft M. Signaling through OX40 (CD134) breaks peripheral T-cell tolerance. Nat Med. 2001;7: 907–912.CrossRefPubMedGoogle Scholar
  55. 55.
    Gri G, Gallo E, Di Carlo E, Musiani P, Colombo MP. OX40 ligand- transduced tumor cell vaccine synergizes with GM-CSF and requires CD40-Apc signaling to boost the host T cell antitumor response. J Immunol. 2003;170:99–106.CrossRefPubMedGoogle Scholar
  56. 56.
    Andarini S, Kikuchi T, Nukiwa M, et al. Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances antitumor immunity of tumor-bearing hosts. Cancer Res. 2004;64: 3281–3287.CrossRefPubMedGoogle Scholar
  57. 57.
    Dannull J, Nair S, Su Z, et al. Enhancing the immunostimulatory function of dendritic cells by transfection with mRNA encoding OX40 ligand. Blood. 2005;105:3206–3213.CrossRefPubMedGoogle Scholar
  58. 58.
    Yanagita S, Hori T, Matsubara Y, Ishikawa T, Uchiyama T. Retroviral transduction of acute myeloid leukaemia-derived dendritic cells with OX40 ligand augments their antigen presenting activity. Br J Haematol. 2004;124:454–462.CrossRefPubMedGoogle Scholar
  59. 59.
    Kaneko H, Hori T, Yanagita S, Kadowaki N, Uchiyama T. Introduction of OX40 ligand into lymphoma cells elicits anti-lymphoma immunity in vivo. Exp Hematol. 2005;33:336–343.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2006

Authors and Affiliations

  1. 1.Department of Hematology and OncologyGraduate School of Medicine, Kyoto UniversitySakyokuJapan

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