OX40 (CD134) and OX40L

  • Michael J. Gough
  • Andrew D. Weinberg
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 647)


The interaction between OX40 and OX40L plays an important role in antigen-specific T-cell expansion and survival. While OX40 is expressed predominantly on T-lymphocytes early after antigen activation, OX40L is expressed on activated antigen presenting cells and endothelial cells within acute inflammatory environments. We discuss here how ligation of OX40 by OX40L leads to enhanced T-cell survival, along with local inflammatory responses that appear critical for both effective T-cell mediated responses and chronic immune pathologies. We describe how interventions that block or mimic the OX40-OX40L interaction can be applied to treat autoimmune diseases or enhance anti-tumor immune responses. The clinically relevant properties of these agents emphasize the importance of this particular TNFSF-TNFSF in health and disease.


Experimental Autoimmune Encephalomyelitis Experimental Allergic Encephalomyelitis OX40L Expression Tumor Necrosis Factor Superfamily OX40 Ligand 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Paterson DJ, Jefferies WA, Green JR et al. Antigens of activated rat T lymphocytes inccluding a molecule of 50,000 Mr detected only on CD4 positive T blasts. Mol Immunol 1987; 24(12):1281–1290.PubMedCrossRefGoogle Scholar
  2. 2.
    Mallett S, Fossum S, Barclay AN. Characterization of the MRC OX40 antigen of activated CD4 positive T lymphocytes—a molecule related to nerve growth factor receptor. EMBO J 1990; 9(4):1063–1068.PubMedGoogle Scholar
  3. 3.
    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 gp.34 EMBO J 1994; 13(17):3992–4001.PubMedGoogle Scholar
  4. 4.
    Baum PR, Gayle RBd, Ramsdell F et al. Identification of OX40 ligand and preliminary characterization of its activities on OX40 receptor. Circ Shock 1994; 44(1):30–34.PubMedGoogle Scholar
  5. 5.
    al_Shamkhani A, Birkeland ML, Puklavec M et al. OX40 is differentially expressed on activated rat and mouse T-cells and is the sole receptor for the OX40 ligand. Eur J Immunol 1996; 26(8):1695–1699.PubMedCrossRefGoogle Scholar
  6. 6.
    Gramaglia I, Weinberg AD, Lemon M et al. Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T-cell responses. J Immunol 1998; 161(12):6510–6517.PubMedGoogle Scholar
  7. 7.
    Evans DE, Prell RA, Thalhofer CJ et al. Engagement of OX40 enhances antigen-specific CD4(+) T-cell mobilization memory development and humoral immunity: comparison of alpha OX-40 with alpha CTLA-4. J Immunol 15 2001; 167(12):6804–6811.Google Scholar
  8. 8.
    Higashimura N, Takasawa N, Tanaka Y et al. Induction of OX40, a receptor of gp, 34 on T-cells by trans-acting transcriptional activator, Tax, of human T-cell leukemia virus type I. Jpn J Cancer Res 1996; 87(3):227–231.PubMedGoogle Scholar
  9. 9.
    Pankow R, Durkop H, Latza U et al. The HTLV-I tax protein transcriptionally modulates OX40 antigen expression. J Immunol 2000; 165(1):263–270.PubMedGoogle Scholar
  10. 10.
    Schubert LA, Cron RQ, Cleary AM et al. A T-cell-specific enhancer of the human CD40 ligand gene. J Biol Chem 2002; 277(9):7386–7395.PubMedCrossRefGoogle Scholar
  11. 11.
    Parra E, Mustelin T, Dohlsten M et al. Identification of a CD28 response element in the CD40 ligand promoter. J Immunol 2001; 166(4):2437–2443.PubMedGoogle Scholar
  12. 12.
    Crist SA, Griffith TS, Ratliff TL. Structure/function analysis of the murine CD95L promoten reveals the identification of a novel transcriptional repressor and functional CD28 response element. J Biol Chem 2003; 278(38):35950–35958.PubMedCrossRefGoogle Scholar
  13. 13.
    Akiba H, Oshima H, Takeda K et al. CD28-independent costimulation of T-cells by OX40 ligand and CD70 on activated B-cells. J Immunol 1999; 162(12):7058–7066.PubMedGoogle Scholar
  14. 14.
    Toennies HM, Green JM, Arch RH. Expression of CD30 and Ox40 on T lymphocyte subsets is controlled by distinct regulatory mechanisms. J Leukoc Biol 2004; 75(2):350–357.PubMedCrossRefGoogle Scholar
  15. 15.
    Horai R, Nakajima A, Habiro K et al. TNF-alpha is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice. J Clin Invest 2004; 114(11):1603–1611.PubMedGoogle Scholar
  16. 16.
    Calderhead DM, Buhlmann JE, van den Eertwegh AJ et al. Cloning of mouse Ox:40 a T-cell activation marker that may mediate T-B-cell interactions. J Immunol 1993; 151(10):5261–5271.PubMedGoogle Scholar
  17. 17.
    Stuber E, Strober W. The T-cell-B-cell interaction via OX40-OX40L is necessary for the T-cell-dependent humoral immune response. J Exp Med 1996; 183(3):979–989.PubMedCrossRefGoogle Scholar
  18. 18.
    Satake Y, Akiba H, Takeda K et al. Characterization of rat OX40 ligand by monoclonal antibody. Biochem Biophys Res Commun 2000; 270(3):1041–1048.PubMedCrossRefGoogle Scholar
  19. 19.
    Kashii Y, Giorda R, Herberman RB et al. Constitutive expression and role of the TNF family ligands in apoptotic killing of tumor cells by human NK cells. J Immunol 1999; 163(10):5358–5366.PubMedGoogle Scholar
  20. 20.
    Zingoni A, Sornasse T, Cocks BG et al. Cross-talk between activated human NK cells and CD4+ T-cells via OX40-OX40 ligand interactions. J Immunol 2004; 173(6):3716–3724.PubMedGoogle Scholar
  21. 21.
    Imura A, Hori T, Imada K et al. The human OX40/gp34 system directly mediates adhesion of activated T-cells to vascular endothelial cells. J Exp Med 1996; 183(5):2185–2195.PubMedCrossRefGoogle Scholar
  22. 22.
    Matsumura Y, Imura A, Hori T et al. Localization of OX40/gp34 in inflammatory skin diseases: a clue to elucidate the interaction between activated T-cells and endothelial cells in infiltration. Arch Dermatol Res 1997; 289(11):653–656.PubMedCrossRefGoogle Scholar
  23. 23.
    Weinberg AD, Wegmann KW, Funatake C et al. 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(3):1818–1826.PubMedGoogle Scholar
  24. 24.
    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(3):2108–2115.PubMedGoogle Scholar
  25. 25.
    Matzinger P. Tolerance, danger and the extended family. Ann Rev Immunol 1994; 12:991–1045.Google Scholar
  26. 26.
    Armitage RJ. Tumor necrosis factor receptor superfamily members and their ligands. Curr Opin Immunol 1994; 6(3):407–413.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhang G. Tumor necrosis factor family ligand-receptor binding. Curr Opin Struct Biol 2004; 14(2):154–160.PubMedCrossRefGoogle Scholar
  28. 28.
    Bodmer JL, Schneider P, Tschopp J. The molecular architecture of the TNF superfamily. Trends Biochem Sci 2002; 27(1):19–26.PubMedCrossRefGoogle Scholar
  29. 29.
    Compaan DM, Hymowitz SG. The crystal structure of the costimulatory OX40-OX40L complex. Structure 2006; 14(8):1321–1330.PubMedCrossRefGoogle Scholar
  30. 30.
    Al-Shamkhani A, Mallett S, Brown MH et al. 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. J Biol Chem 1997; 272(8):5275–5282.PubMedCrossRefGoogle Scholar
  31. 31.
    Wajant H, Henkler F, Scheurich P. The TNF-receptor-associated factor family: scaffold molecules for cytokine. Cell Signal 2001; 13(6):389–400.PubMedCrossRefGoogle Scholar
  32. 32.
    Chung JY, Park YC, Ye H et al. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci 2002; 115(Pt 4):679–688.PubMedGoogle Scholar
  33. 33.
    Prell RA, Evans DE, Thalhofer C et al. OX40-mediated memory T-cell generation is TNF receptor-associated factor 2 dependent. J Immunol 2003; 171(11):5997–6005.PubMedGoogle Scholar
  34. 34.
    So T, Salek-Ardakani S, Nakano H et al. TNF receptor-associated factor 5 limits the induction of Th2 immune responses. J Immunol 2004; 172(7):4292–4297.PubMedGoogle Scholar
  35. 35.
    Hauer J, Puschner S, Ramakrishnan P et al. TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs. Proc Natl Acad Sci USA; 102(8):2874–2879.Google Scholar
  36. 36.
    Kawamata S, Hori T, Imura A et al. Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2-and TRAF5-mediated NF-kappaB activation. J Biol Chem 1998; 273(10):5808–5814.PubMedCrossRefGoogle Scholar
  37. 37.
    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 activated nuclear factor kappaB. Mol Cell Biol 1998; 18(1):558–565.PubMedGoogle Scholar
  38. 38.
    Rogers PR, Croft M. CD28, Ox-40, LFA-1 and CD4 modulation of Th1/Th2 differentiation is directly dependent on the dose of antigen. J Immunol 2000; 164(6):2955–2963.PubMedGoogle Scholar
  39. 39.
    Park YC, Burkitt V, Villa AR et al. Structural basis for self-association and receptor recognition of human TRAF2. Nature 1999; 398(6727):533–538.PubMedCrossRefGoogle Scholar
  40. 40.
    McWhirter SM, Pullen SS, Holton JM et al. Crystallographic analysis of CD40 recognition and signaling by human TRAF2. Proc Natl Acad Sci USA 1999; 96(15):8408–8413.PubMedCrossRefGoogle Scholar
  41. 41.
    Mestas J, Crampton SP, Hori T et al. Endothelial cell costimulation through OX40 augments and prolongs T-cell cytokine synthesis by stabilization of cytokine mRNA. Int Immunol 2005; 17(6):737–747.PubMedCrossRefGoogle Scholar
  42. 42.
    Song J, Salek-Ardakani S, Rogers PR et al. The costimulation-regulated duration of PKB activation controls T-cell longevity. Nat Immunol 2004; 5(2):150–158.PubMedCrossRefGoogle Scholar
  43. 43.
    Jones RG, Parsons M, Bonnard M et al. Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation and Bcl-X(L) levels in vivo. J Exp Med 2000; 191(10):1721–1734.PubMedCrossRefGoogle Scholar
  44. 44.
    Rogers PR, Song J, Gramaglia I et al. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T-cells. Immunity 2001; 15(3):445–455.PubMedCrossRefGoogle Scholar
  45. 45.
    Song A, Tang X, Harms KM, Croft M. OX40 and Bcl-xL Promote the Persistence of CD8 T-cells to Recall Tumor-Associated Antigen. J Immunol 2005; 175(6):3534–3541.PubMedGoogle Scholar
  46. 46.
    Huddleston CA, Weinberg AD, Parker DC. OX40 (CD134) engagement drives differentiation of CD4+ T-cells to effector cells. Eur J Immunol 2006; 36(5):1093–1103.PubMedCrossRefGoogle Scholar
  47. 47.
    Hurlin PJ, Queva C, Koskinen PJ et al. Mad3 and Mad:4 novel Max-interacting transcriptional repressors that suppress c-myc dependent transformation and are expressed during neural and epidermal differentiation. EMBO J 1996; 15(8):2030.PubMedGoogle Scholar
  48. 48.
    Maxwell JR, Weinberg A, Prell RA et al. Danger and OX40 receptor signaling synergize to enhance memory T-cell survival by inhibiting peripheral deletion. J Immunol 2000; 164(1):107–112.PubMedGoogle Scholar
  49. 49.
    Gramaglia I, Jember A, Pippig SD et al. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J Immunol 2000; 165(6):3043–3050.PubMedGoogle Scholar
  50. 50.
    Weatherill AR, Maxwell JR, Takahashi C et al. OX40 ligation enhances cell cycle turnover of Ag-activated CD4 T-cells in vivo. Cell Immunol 2001; 209(1):63–75.PubMedCrossRefGoogle Scholar
  51. 51.
    Ruby CE, Redmond WL, Haley D et al. Anti-OX40 stimulation in vivo enhances CD8(+) memory T-cell survival and significantly increases recall responses. Eur J Immunol 2007; 37(1):157–166.PubMedCrossRefGoogle Scholar
  52. 52.
    Lee SW, Park Y, Song A et al. Functional dichotomy between OX40 and 4-1BB in modulating effector CD8 T-cell responses. J Immunol 2006; 177(7):4464–4472.PubMedGoogle Scholar
  53. 53.
    Fujita T, Ukyo N, Hori T et al. Functional characterization of OX40 expressed on human CD8+ T-cells. Immunol Lett 2006; 106(1):27–33.PubMedCrossRefGoogle Scholar
  54. 54.
    Serghides L, Bukczynski J, Wen T et al. Evaluation of OX40 ligand as a costimulator of human antiviral memory CD8 T-cell responses: comparison with B7.1 and 4-1BBL. J Immunol 2005; 175(10):6368–6377.PubMedGoogle Scholar
  55. 55.
    Hendriks J, Xiao Y, Rossen JW et al. 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. J Immunol 2005; 175(3):1665–1676.PubMedGoogle Scholar
  56. 56.
    Chen AI, McAdam AJ, Buhlmann JE et al. Ox40-ligand has a critical costimulatory role in dendritic cell: T-cell interactions. Immunity 1999; 11(6):689–698.PubMedCrossRefGoogle Scholar
  57. 57.
    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(2):375–380.PubMedCrossRefGoogle Scholar
  58. 58.
    Flynn S, Toellner KM, Raykundalia C et al. 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. J Exp Med 1998; 188(2):297–304.PubMedCrossRefGoogle Scholar
  59. 59.
    Ohshima Y, Yang LP, Uchiyama T et al. OX40 costimulation enhances interleukin-4 (IL-4) expression at priming and promotes the differentiation of naive human CD4(+) T-cells into high IL-4-producing effectors. Blood 1998; 92(9):3338–3345.PubMedGoogle Scholar
  60. 60.
    Linton PJ, Bautista B, Biederman E et al. Costimulation via OX40L expressed by B-cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo. J Exp Med 2003; 197(7):875–883.PubMedCrossRefGoogle Scholar
  61. 61.
    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(2):365–374.PubMedCrossRefGoogle Scholar
  62. 62.
    Gramaglia I, Jember A, Pippig SD et al. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J Immunol 2000; 165(6):3043–3050.PubMedGoogle Scholar
  63. 63.
    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(6):699–708.PubMedCrossRefGoogle Scholar
  64. 64.
    Croft M, Duncan DD, Swain SL. Response of naive antigen-specific CD4+ T-cells in vitro: characteristics and antigen-presenting cell requirements. J Exp Med 1992; 176(5):1431–1437.PubMedCrossRefGoogle Scholar
  65. 65.
    Ohshima Y, Tanaka Y, Tozawa H et al. Expression and function of OX40 ligand on human dendritic cells. J Immunol 1997; 159(8):3838–3848.PubMedGoogle Scholar
  66. 66.
    Pippig SD, Pena-Rossi C, Long J et al. Robust B-cell immunity but impaired T-cell proliferation in the absence of CD134 (OX40). J Immunol 1999; 163(12):6520–6529.PubMedGoogle Scholar
  67. 67.
    Dawicki W, Bertram EM, Sharpe AH, Watts TH. 4-1BB and OX40 act independently to facilitate robust CD8 and CD4 recall responses. J Immunol 2004; 173(10):5944–5951.PubMedGoogle Scholar
  68. 68.
    Stuber E, Neurath M, Calderhead D et al. 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(5):507–521.PubMedCrossRefGoogle Scholar
  69. 69.
    Morimoto S, Kanno Y, Tanaka Y et al. CD134L engagement enhances human B cell Ig production: CD154/CD40, CD70/CD27 and CD134/CD134L interactions coordinately regulate T-cell-dependent B-cell responses. J Immunol 2000; 164(8):4097–4104.PubMedGoogle Scholar
  70. 70.
    Matsumura Y, Hori T, Kawamata S et al. Intracellular signaling of gp,34 the OX40 ligand: induction of c-jun and c-fos mRNA expression through gp34 upon binding of its receptor, OX40. J Immunol 1999; 163(6):3007–3011.PubMedGoogle Scholar
  71. 71.
    Kotani A, Hori T, Matsumura Y et al. Signaling of gp34, (OX40 ligand) induces vascular endothelial cells to produce a CC chemokine RANTES/CCL5. Immunol Lett 2002; 84(1):1–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Eissner G, Kolch W, Scheurich P. Ligands working as receptors: reverse signaling by members of the TNF superfamily enhance the plasticity of the immune system. Cytokine Growth Factor Rev 2004; 15(5):353–366.PubMedCrossRefGoogle Scholar
  73. 73.
    Langstein J, Michel J, Fritsche J et al. CD137 (ILA/4-1BB), a member of the TNF receptor family, induces monocyte activation via bidirectional signaling. J Immunol 1998; 160(5):2488–2494.PubMedGoogle Scholar
  74. 74.
    Wiley SR, Goodwin RG, Smith CA. Reverse signaling via CD30 ligand. J Immunol 1996; 157(8):3635–3639.PubMedGoogle Scholar
  75. 75.
    Suzuki I, Martin S, Boursalian et al. Fas ligand costimulates the in vivo proliferation of CD8+ T-cells. J Immunol 2000; 165(10):5537–5543.PubMedGoogle Scholar
  76. 76.
    Sun M, Ames KT, Suzuki I et al. The cytoplasmic domain of Fas ligand costimulates TCR signals. J Immunol 2006; 177(3):1481–1491.PubMedGoogle Scholar
  77. 77.
    Grewal IS, Xu J, Flavell RA. Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature 1995; 378(6557):617–620.PubMedCrossRefGoogle Scholar
  78. 78.
    van Essen D, Kikutani H, Gray D. CD40 ligand-transduced costimulation of T-cells in the development of helper function. Nature 1995; 378(6557):620–623.PubMedCrossRefGoogle Scholar
  79. 79.
    Matsumura Y, Hori T, Nishigori C et al. Expression of CD134 and CD134 ligand in lesional and nonlesional psoriatic skin. Arch Dermatol Res 2003; 294(12):563–566.PubMedGoogle Scholar
  80. 80.
    Weinberg AD, Wallin JJ, Jones RE et al. Target organ-specific up-regulation of the MRC OX-40 marker and selective production of Th 1 lymphokine mRNA by encephalitogenic T-helper cells isolated from the spinal cord of rats with experimental autoimmune enciphalomyelitis. Journal of Immunology 1994; 152:4712–4721.Google Scholar
  81. 81.
    Souza HS, Elia CC, Spencer J et al. Expression of lymphocyte-endothelial receptor-ligand pairs, alpha-4beta7/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease. Gut 1999; 45(9):856–863.PubMedCrossRefGoogle Scholar
  82. 82.
    Aten J, Roos A, Claessen N et al. Strong and selective glomerular localization of CD134 ligand and TNF receptor-1 in proliferative lupus nephritis. J Am Soc Nephrol 2000; 11(8):1426–1438.PubMedGoogle Scholar
  83. 83.
    Endres R, Luz A, Schulze H et al. Listeripsis in p47(phox-/-) and TRp55-/-mice: protection despite absence of ROI and susceptibility despite presence of RNI. Immunity 1997; 7(3):419–432.PubMedCrossRefGoogle Scholar
  84. 84.
    Weinberg AD. Antibodies to OX-40 (CD134) can identify and eliminate autoreactive T-cells: implications for human autoimmune disease. Mol Med Today 1998; 4(2):76–83.PubMedCrossRefGoogle Scholar
  85. 85.
    Weinberg AD, Bourdette DN, Sullivan TJ et al. Selective depletion of myelin-reactive T-cells with the anti-OX-40 antibody ameliorates autoimmune encephalomyelitis. Nat Med 1996; 2(2):183–189.PubMedCrossRefGoogle Scholar
  86. 86.
    Weinberg AD, Lemon M, Jones AJ et al. OX-40 antibody enhances for autoantigen specific V beta 8.2+T-cells within the spinal cord of Lewis rats with autoimmune encephalomyelitis. J Neurosci Res 1996; 43(1):42–49.PubMedCrossRefGoogle Scholar
  87. 87.
    Weinberg AD, Wallin JJ, Jones RE et al. Target organ-specific up-regulation of the MRC OX-40 marker and selective production of Th1 lymphokine mRNA by encephalitogenic T-helper cells isolated from the spinal cord of rats with experimental autoimmune encephalomyelitis. J Immunol 1994; 152(9):4712–4721.PubMedGoogle Scholar
  88. 88.
    Vetto JT, Lum S, Morris A et al. Presence of the T-cell activation marker OX-40 on tumor infiltrating lymphocytes and draining lymph node cells from patients with melanoma and head and neck cancers. Am J Surg 1997; 174(3):258–265.PubMedCrossRefGoogle Scholar
  89. 89.
    Durkop H, Latza U, Himmelreich P et al. Expression of the human OX40 (hOX40) antigen in normal and neoplastic tissues. Br J Haematol 1995; 91(4):927–931.PubMedCrossRefGoogle Scholar
  90. 90.
    Ladanyi A, Somlai B, Gilde K et al. T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res 2004; 10(2):521–530.PubMedCrossRefGoogle Scholar
  91. 91.
    Ramstad T, Lawnicki L, Vetto J et al. Immunohistochemical analysis of primary breast tumors and tumor-draining lymph nodes by means of the T-cell costimulatory molecule OX-40. Am J Surg 2000; 179(5):400–406.PubMedCrossRefGoogle Scholar
  92. 92.
    Petty JK, He K, Corless CL et al. Survival in human colorectal cancer correlates with expression of the T-cell costimulatory molecule OX-40 (CD134). Am J Surg 2002; 183(5):512–518.PubMedCrossRefGoogle Scholar
  93. 93.
    Mottonen M, Heikkinen J, Mustonen L et al. CD4+ CD25+ T-cells with the phenotypic and functional characteristics of regulatory T-cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol 2005; 140(2):360–367.PubMedCrossRefGoogle Scholar
  94. 94.
    Valzasina B, Guiducci C, Dislich H et al. Triggering of OX40 (CD134) on CD4(+)CD25+ T-cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood 2005; 105(7):2845–2851.PubMedCrossRefGoogle Scholar
  95. 95.
    Nolte-’t Hoen EN, Wagenaar-Hilbers JP, Boot EP et al. Identification of a CD4+CD25+ T-cell subset committed in vivo to suppress antigen-specific T-cell responses without additional stimulation. Eur J Immunol 2004; 34(11):3016–3027.PubMedCrossRefGoogle Scholar
  96. 96.
    Curiel TJ, Coukos G, Zou L et al. Specific recruitment of regulatory T-cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10(9):942–949.PubMedCrossRefGoogle Scholar
  97. 97.
    Sato E, Olson SH, Ahn J et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T-cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 2005; 102(51):18538–18543.PubMedCrossRefGoogle Scholar
  98. 98.
    Wolf D, Wolf AM, Rumpold H et al. The expression of the regulatory T-cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 2005; 11(23):8326–8331.PubMedCrossRefGoogle Scholar
  99. 99.
    Badoual C, Hans S, Rodriguez J et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 2006; 12(2):465–472.PubMedCrossRefGoogle Scholar
  100. 100.
    Takeda I, Ine S, Killeen N et al. Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T-cells. J Immunol 2004; 172(6):3580–3589.PubMedGoogle Scholar
  101. 101.
    Ito T, Wang YH, Duramad O et al. OX40 ligand shuts down IL-10-producing regulatory T-cells. Proc Natl Acad Sci USA 2006; 103(35):13138–13143.PubMedCrossRefGoogle Scholar
  102. 102.
    Humphreys IR, Walzl G, Edwards L et al. A critical role for OX40 in T-cell-mediated immunopathology during lung viral infection. J Exp Med 2003; 198(8):1237–1242.PubMedCrossRefGoogle Scholar
  103. 103.
    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(12):6125–6132.PubMedGoogle Scholar
  104. 104.
    Pakala SV, Bansal-Pakala P, Halteman BS et al. Prevention of diabetes in NOD mice at a late stage by targeting OX40/OX40 ligand interactions. Eur J Immunol 2004; 34(11):3039–3046.PubMedCrossRefGoogle Scholar
  105. 105.
    Obermeier F, Schwarz H, Dunger N et al. OX40/OX40L interaction induces the expression of CXCR5 and contributes to chronic colitis induced by dextran sulfate sodium in mice. Eur J Immunol 2003; 33(12):3265–3274.PubMedCrossRefGoogle Scholar
  106. 106.
    Malmstrom V, Shipton D, Singh B et al. Cd1341 expression on dendritic cells in the mesenteric lymph nodes drives colitis in T-cell-restored scid mice. J Immunol 2001; 166(11):6972–6981.PubMedGoogle Scholar
  107. 107.
    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(10):2815–2823.PubMedCrossRefGoogle Scholar
  108. 108.
    Kulbe H, Thompson R, Wilson JL et al. The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res 2007; 67(2):585–592.PubMedCrossRefGoogle Scholar
  109. 109.
    de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 2006; 6(1):24–37.PubMedCrossRefGoogle Scholar
  110. 110.
    Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420(6917):860–867.PubMedCrossRefGoogle Scholar
  111. 111.
    Gough M, Crittenden M, Thanarajasingam U et al. Gene therapy to manipulate effector T-cell trafficking to tumors for immunotherapy. J Immunol 2005; 174(9):5766–5773.PubMedGoogle Scholar
  112. 112.
    Morris A, Vetto JT, Ramstad T et al. Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo. Breast Cancer Res Treat 2001; 67(1):71–80.PubMedCrossRefGoogle Scholar
  113. 113.
    Kjaergaard J, Peng L, Cohen PA et al. Augmentation versus inhibition: effects of conjunctional OX-40 receptor monoclonal antibody and IL-2 treatment on adoptive immunotherapy of advanced tumor. J Immunol 2001; 167(11):6669–6677.PubMedGoogle Scholar
  114. 114.
    Weinberg AD, Rivera MM, Prell R et al. Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol 2000; 164(4):2160–2169.PubMedGoogle Scholar
  115. 115.
    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(9):3281–3287.PubMedCrossRefGoogle Scholar
  116. 116.
    Gri G, Gallo E, Di Carlo E et al. 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(1):99–106.PubMedGoogle Scholar
  117. 117.
    Lathrop SK, Huddleston CA, Dullforce PA et al. A signal through OX40 (CD134) allows anergic, autoreactive T-cells to acquire effector cell functions. J Immunol 2004; 172:6735–6743.PubMedGoogle Scholar
  118. 118.
    Kuniyasu Y, Takahashi T, Itoh M et al. Naturally anergic and suppressive CD25(+)CD4(+) T-cells as a functionally and phenotypically distinct immunoregulatory T-cell subpopulation. Int Immunol 2000; 12(8):1145–1155.PubMedCrossRefGoogle Scholar
  119. 119.
    Sakaguchi S, Sakaguchi N, Shimizu J et al. Immunologic to lerance maintained by CD25+ CD4+ regulatory T-cells: their common role in controlling autoimmunity, tumor immunity and transplantation tolerance. Immunol Rev 2001; 182:18–32.PubMedCrossRefGoogle Scholar
  120. 120.
    Weinberg AD, Thalhofer C, Morris N et al. Anti-OX40 (CD134) administration to nonhuman primates: immunostimulatory effects and toxicokinetic study. J Immunother 2006; 29(6):575–585.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Michael J. Gough
    • 1
  • Andrew D. Weinberg
    • 1
  1. 1.Robert W. Franz Cancer Center, Earle A. Chiles Research InstituteProvidence Portland Medical CenterPortlandUSA

Personalised recommendations