Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

OX40 Signaling Renders Adult T-Cell Leukemia Cells Resistant to Fas-Induced Apoptosis

  • 56 Accesses

  • 6 Citations


We reported previously that OX40, a member of the tumor necrosis factor receptor family, is expressed constitutively on fresh leukemia/lymphoma cells isolated from patients with adult T-cell leukemia (ATL). In this study, we tested whether OX40 signaling affects the Fas-mediated apoptosis of fresh ATL cells isolated from 7 patients (3 acute type, 3 chronic type, and 1 smoldering type). In all these patients, the coculture of ATL cells with MMCE/OX40 ligand gp34, a stable human gp34 transfectant of a mouse epithelial cell line, resulted in a decrease in the percentage of apoptotic cells after treatment with anti-Fas monoclonal antibody, compared to coculture with MMCE/mock controls. Similar findings were obtained in OX40+_ human T-cell leukemia virus type I-transformed T-cell lines. To elucidate the molecular mechanism of this phenomenon, we used Kit225/OX40, a stable OX40 transfectant of an IL-2-dependent T-cell line, and its deletion mutant, Kit225/del-OX40, in which the intracytoplasmic domain of OX40 had been deleted. Coculture with MMCE/gp34 inhibited the apoptosis of Kit225/OX40, but Kit225/del-OX40 apoptosis was hardly affected.These results suggest that ATL cells may escape Fas-mediated destruction of the immune system through OX40 signaling.

This is a preview of subscription content, log in to check access.


  1. 1.

    Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T cell leukemia: clinical and hematologic features of 16 cases.Blood. 1977;50:481–492.

  2. 2.

    Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type-C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.Proc Natl Acad Sci U S A. 1980;77:7415–7419.

  3. 3.

    Uchiyama T. Human T cell leukemia virus type I (HTLV-I) and human diseases.Annu Rev Immunol. 1997;15:15–37.

  4. 4.

    Yamaguchi K. Human T-lymphotropic virus type I in Japan.Lancet. 1994;343:213–216.

  5. 5.

    Imura A, Hori T, Imada K, et al. OX40 expressed on fresh leukemic cells from adult T-cell leukemia patients mediates cell adhesion to vascular endothelial cells: implication for the possible involvement of OX40 in leukemic cell infiltration.Blood. 1997;89:2951–2958.

  6. 6.

    Tanaka Y, Inoi T, Tozawa H, Yamamoto N, Hinuma Y. A glycoprotein antigen detected with new monoclonal antibodies on the surface of human lymphocytes infected with human T-cell leukemia virus type-I (HTLV-I).Int J Cancer. 1985;36:549–555.

  7. 7.

    Tozawa H, Andoh S, Takayama Y, et al. Species-dependent antigenicity of the 34-kDa glycoprotein found on the membrane of various primate lymphocytes transformed by human T-cell leukemia virus type-I (HTLV-I) and simian T-cell leukemia virus (STLV-I).Int J Cancer. 1988;41:231–238.

  8. 8.

    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.

  9. 9.

    Paterson DJ, Jefferies WA, Green JR, et al. Antigens of activated rat T lymphocytes including a molecule of 50,000 Mr detected only on CD4 positive T blasts.Mol Immunol. 1987;24:1281–1290.

  10. 10.

    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;9:1063–1068.

  11. 11.

    Calderhead DM, Buhlmann JE, van den Eertwegh AJM, Claassen E, Noelle RJ, Fell HP. Cloning of mouse OX40: a T cell activation marker that may mediate T-B cell interactions.J Immunol. 1993;151:5261–5271.

  12. 12.

    Latza U, Durkop H, Schnittger S, et al. The human OX40 homolog: cDNA structure, expression and chromosomal assignment of the ACT35 antigen.Eur J Immunol. 1994;24:677–683.

  13. 13.

    Gruss HJ, Dower SK. Tumor necrosis factor ligand superfamily: involvement in pathology of malignant lymphomas.Blood. 1995;85:3378–3404.

  14. 14.

    Beg AA, Baltimore D. An essential role for NF-κB in preventing TNF-α-induced cell death.Science. 1996;274:782–784.

  15. 15.

    Liu ZG, Hsu H, Goeddel DV, Karin M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death.Cell. 1996;87:565–576.

  16. 16.

    Van AD, Martin SJ, Kafri T, Green DR, Verma IM. Suppression of TNF-α-induced apoptosis by NF-κB.Science. 1996;274:787–789.

  17. 17.

    Sha WC. Regulation of immune responses by NF-κB/Rel transcription factors.J Exp Med. 1998;187:143–146.

  18. 18.

    Kawamata S, Hori T, Imura A, Takaori-Kondo A, Uchiyama T. Activation of OX40 signal transduction pathways leads to TRAF2-and TRAF5-mediated NF-κB activation.J Biol Chem. 1998;273:5808–5814.

  19. 19.

    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;67:111–118.

  20. 20.

    Hori T, Uchiyama T, Tsudo M, et al. Establishment of an interleukin 2-dependent human T cell line from a patient with T cell chronic lymphocyte leukemia who is not infected with human T cell leukemia/lymphoma virus.Blood. 1987;70:1069–1072.

  21. 21.

    Matsumura Y, Hori T, Kawamata S, Imura A, Uchiyama T. Intracellular signaling of gp34, the OX40 ligand: induction of c-jun and c-fos mRNA expression through gp34 upon binding of its receptor, OX40.J Immunol. 1999;163:3007–3011.

  22. 22.

    Koopman G, Reutelingsperger CPM, Kuijten GAM, Keehnen RMJ, Pals ST, van Oers MHJ. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis.Blood. 1994;84:1415–1420.

  23. 23.

    Ishikawa T, Imura A, Tanaka H, Shirane H, Okuma M, Uchiyama T. E-selectin and vascular cell adhesion molecule-1 mediate adult T cell leukemia cell adhesion to endothelial cells.Blood. 1993;82:1590–1598.

  24. 24.

    Parker CE, Nightingale S, Taylor GP, Weber J, Bangham CR. Circulating anti-Tax cytotoxic T lymphocytes from human T-cell leukemia virus type I-infected people, with and without tropical spastic paraparesis, recognize multiple epitopes simultaneously.J Virol. 1994;68:2860–2868.

  25. 25.

    Tamiya S, Etoh K, Suzushima H, Takatsuki K, Matsuoka M. Mutation of CD95 (Fas/Apo-1) gene in adult T-cell leukemia cells.Blood. 1998;91:3935–3842.

  26. 26.

    Copeland KFT, Haaksma AGM, Goudsmit J, Krammer PH, Heeney JL. Inhibition of apoptosis in T cells expressing human T cell leukemia virus type I Tax.AIDS Res Hum Retroviruses. 1994;10:1259–1268.

  27. 27.

    Pimentel-Muiños FX, Seed B. Regulated commitment of TNF receptor signaling: a molecular switch for death or activation.Immunity. 1999;11:783–793.

  28. 28.

    Baldwin ASJ. The NF-κB and IκB proteins: new discoveries and insights.Annu Rev Immunol. 1996;14:649–681.

  29. 29.

    Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation.Cell. 1995;81:495–504.

  30. 30.

    Hsu H, Shu HB, Pan MG, Goeddel DV. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways.Cell. 1996;84:299–308.

  31. 31.

    Mori N, Fujii M, Ikeda S, et al. Constitutive activation of NF-κB in primary adult T-cell leukemia cells.Blood. 1999;93:2360–2368.

  32. 32.

    Nakamura M, Takasawa N, Ohbo K, et al. HTLV-I Tax trans-activation and cell growth signaling.Leukemia. 1997;3:7–9.

  33. 33.

    Higashimura N, Takasawa N, Tanaka Y, Nakamura M, Sugamura K. Induction of OX40, a receptor of gp34, on T cells by trans-acting transcriptional activator, Tax, of human T-cell leukemia virus type I.Jpn J Cancer Res. 1996;87:227–231.

  34. 34.

    Kato T, Furumoto H, Kamada M, et al. Immunological functions of adult T cell leukemia cells of a patient complicated with synchronous double primary gynecologic cancer.J Med Invest. 1997;44:99–102.

  35. 35.

    Kamihara S, Yamada Y, Tomonaga M, Sugahara K, Tsuruda K. Discrepant expression of membrane and soluble isoforms of Fas(CD95/APO-1) in adult T-cell leukemia: soluble Fas isoform is an independent risk factor for prognosis.Br J Haematol. 1999;107:851–860.

  36. 36.

    Jeffrey SF, Underhill LH. The tumor necrosis factor ligand and receptor families.New Engl J Med. 1996;334:1717–1725.

  37. 37.

    Khoshnan A, Tindell C, Laux I, Bae D, Bennet B, Nel AE. The NF-κB cascade is important in Bcl-xL expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4+ lymphocytes.J Immunol. 2000;165:1743–1754.

  38. 38.

    Rogers PR, Song J, Gramaglia I, Killeen N, Groft M. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells.Immunity. 2001;15:445–455.

  39. 39.

    Baum PR, Gayle RB III, Ramsdell F, et al. Molecular characterization of murine and human OX40/OX40 ligand systems: identification of a human OX40 ligand as the HTLV-I-regulated protein gp34.EMBO J. 1994;13:3992–4001.

  40. 40.

    Godfrey WR, Fagnoni FF, Harara MA, Buck D, Engleman EG. Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor.J Exp Med. 1994;180:757–762.

  41. 41.

    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;183:2185–2195.

  42. 42.

    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.

  43. 43.

    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.

  44. 44.

    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;162:7058–7066.

  45. 45.

    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;91:365–374.

  46. 46.

    Peter L. Role of OX40 signals in coordinating CD4 T cell selection, migration, and cytokine differentiation in T helper (Th)1 and Th2 cells.J Exp Med. 2000;191:201–206.

Download references

Author information

Correspondence to Akane Kunitomi or Toshiyuki Hori or Michiyuki Maeda or Takashi Uchiyama.

About this article

Cite this article

Kunitomi, A., Hori, T., Maeda, M. et al. OX40 Signaling Renders Adult T-Cell Leukemia Cells Resistant to Fas-Induced Apoptosis. Int J Hematol 76, 260–266 (2002).

Download citation

Key words

  • OX40
  • ATL
  • Apoptosis