Advertisement

Archives of Virology

, Volume 159, Issue 7, pp 1849–1856 | Cite as

Development of T cell lymphoma in HTLV-1 bZIP factor and Tax double transgenic mice

  • Tiejun Zhao
  • Yorifumi Satou
  • Masao Matsuoka
Brief Report

Abstract

Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATL cells possess a CD4+ CD25+ phenotype, similar to that of regulatory T cells (Tregs). Tax has been reported to play a crucial role in the leukemogenesis of HTLV-1. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the viral genomic RNA, is expressed in all ATL cases and induces neoplastic and inflammatory disease in vivo. To test whether HBZ and Tax are both required for T cell malignancy, we generated HBZ/Tax double transgenic mice in which HBZ and Tax are expressed exclusively in CD4+ T cells. Survival was much reduced in HBZ/Tax double-transgenic mice compared with wild type littermates. Transgenic expression of HBZ and Tax induced skin lesions and T-cell lymphoma in mice, resembling diseases observed in HTLV-1 infected individuals. However, Tax single transgenic mice did not develop major health problems. In addition, memory CD4+ T cells and Foxp3+ Treg cells counts were increased in HBZ/Tax double transgenic mice, and their proliferation was enhanced. There was very little difference between HBZ single and HBZ/Tax double transgenic mice. Taken together, these results show that HBZ, in addition to Tax, plays a critical role in T-cell lymphoma arising from HTLV-1 infection.

Keywords

HTLV-1 HBZ Tax Transgenic mice Lymphoma 

Notes

Acknowledgments

This work was supported by a grant from National Natural Science Foundation of China to TZ (No.31200128); a Grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan to MM. The authors thank Aaron Coutts for proofreading the manuscript.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

705_2014_2099_MOESM1_ESM.pptx (76 kb)
Supplemental Fig. 1 Tax could not induce Foxp3 expression. ATL-43T cells, an ATL cell line, were transduced with lentiviral vector encoding Tax, or with empty vector. One and two days after infection, cells were stained with anti-Foxp3 in addition to anti-NGFR and then analyzed by flow cytometry. (PPTX 76 kb)

References

  1. 1.
    Arnulf B, Villemain A, Nicot C, Mordelet E, Charneau P, Kersual J, Zermati Y, Mauviel A, Bazarbachi A, Hermine O (2002) Human T-cell lymphotropic virus oncoprotein Tax represses TGF-beta 1 signaling in human T cells via c-Jun activation: a potential mechanism of HTLV-I leukemogenesis. Blood 100:4129–4138PubMedCrossRefGoogle Scholar
  2. 2.
    Basbous J, Arpin C, Gaudray G, Piechaczyk M, Devaux C, Mesnard JM (2003) The HBZ factor of human T-cell leukemia virus type I dimerizes with transcription factors JunB and c-Jun and modulates their transcriptional activity. J Biol Chem 278:43620–43627PubMedCrossRefGoogle Scholar
  3. 3.
    Fan J, Ma G, Nosaka K, Tanabe J, Satou Y, Koito A, Wain-Hobson S, Vartanian JP, Matsuoka M (2010) APOBEC3G generates nonsense mutations in human T-cell leukemia virus type 1 proviral genomes in vivo. J Virol 84:7278–7287PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Gaudray G, Gachon F, Basbous J, Biard-Piechaczyk M, Devaux C, Mesnard JM (2002) The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol 76:12813–12822PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Grassmann R, Aboud M, Jeang KT (2005) Molecular mechanisms of cellular transformation by HTLV-1 Tax. Oncogene 24:5976–5985PubMedCrossRefGoogle Scholar
  6. 6.
    Grossman WJ, Kimata JT, Wong FH, Zutter M, Ley TJ, Ratner L (1995) Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type I. Proc Natl Acad Sci USA 92:1057–1061PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Hagiya K, Yasunaga J, Satou Y, Ohshima K, Matsuoka M (2011) ATF3, an HTLV-1 bZip factor binding protein, promotes proliferation of adult T-cell leukemia cells. Retrovirology 8:19PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Hasegawa H, Sawa H, Lewis MJ, Orba Y, Sheehy N, Yamamoto Y, Ichinohe T, Tsunetsugu-Yokota Y, Katano H, Takahashi H, Matsuda J, Sata T, Kurata T, Nagashima K, Hall WW (2006) Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I. Nat Med 12:466–472PubMedCrossRefGoogle Scholar
  9. 9.
    Kannagi M, Harada S, Maruyama I, Inoko H, Igarashi H, Kuwashima G, Sato S, Morita M, Kidokoro M, Sugimoto M et al (1991) Predominant recognition of human T cell leukemia virus type I (HTLV-I) pX gene products by human CD8+ cytotoxic T cells directed against HTLV-I-infected cells. Int Immunol 3:761–767PubMedCrossRefGoogle Scholar
  10. 10.
    Karube K, Ohshima K, Tsuchiya T, Yamaguchi T, Kawano R, Suzumiya J, Utsunomiya A, Harada M, Kikuchi M (2004) Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells. Br J Haematol 126:81–84PubMedCrossRefGoogle Scholar
  11. 11.
    Lee DK, Kim BC, Brady JN, Jeang KT, Kim SJ (2002) Human T-cell lymphotropic virus type 1 tax inhibits transforming growth factor-beta signaling by blocking the association of Smad proteins with Smad-binding element. J Biol Chem 277:33766–33775PubMedCrossRefGoogle Scholar
  12. 12.
    Lemasson I, Lewis MR, Polakowski N, Hivin P, Cavanagh MH, Thebault S, Barbeau B, Nyborg JK, Mesnard JM (2007) Human T-cell leukemia virus type 1 (HTLV-1) bZIP protein interacts with the cellular transcription factor CREB to inhibit HTLV-1 transcription. J Virol 81:1543–1553PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Ma G, Yasunaga J, Fan J, Yanagawa S, Matsuoka M (2012) HTLV-1 bZIP factor dysregulates the Wnt pathways to support proliferation and migration of adult T-cell leukemia cells. Oncogene 32:4222–4230PubMedCrossRefGoogle Scholar
  14. 14.
    Matsumoto J, Ohshima T, Isono O, Shimotohno K (2005) HTLV-1 HBZ suppresses AP-1 activity by impairing both the DNA-binding ability and the stability of c-Jun protein. Oncogene 24:1001–1010PubMedCrossRefGoogle Scholar
  15. 15.
    Matsuoka M, Jeang KT (2007) Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer 7:270–280PubMedCrossRefGoogle Scholar
  16. 16.
    Matsuoka M, Green PL (2009) The HBZ gene, a key player in HTLV-1 pathogenesis. Retrovirology 6:71PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Mori N, Morishita M, Tsukazaki T, Giam CZ, Kumatori A, Tanaka Y, Yamamoto N (2001) Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor beta signaling through interaction with CREB-binding protein/p300. Blood 97:2137–2144PubMedCrossRefGoogle Scholar
  18. 18.
    Nerenberg M, Hinrichs SH, Reynolds RK, Khoury G, Jay G (1987) The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science 237:1324–1329PubMedCrossRefGoogle Scholar
  19. 19.
    Nicot C, Harrod RL, Ciminale V, Franchini G (2005) Human T-cell leukemia/lymphoma virus type 1 nonstructural genes and their functions. Oncogene 24:6026–6034PubMedCrossRefGoogle Scholar
  20. 20.
    Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC (1980) 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 USA 77:7415–7419PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Satou Y, Yasunaga J, Yoshida M, Matsuoka M (2006) HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. Proc Natl Acad Sci USA 103:720–725PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Satou Y, Yasunaga J, Zhao T, Yoshida M, Miyazato P, Takai K, Shimizu K, Ohshima K, Green PL, Ohkura N, Yamaguchi T, Ono M, Sakaguchi S, Matsuoka M (2011) HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. Plos Pathogens 7:e1001274PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Toulza F, Heaps A, Tanaka Y, Taylor GP, Bangham CR (2008) High frequency of CD4+ FoxP3+ cells in HTLV-1 infection: inverse correlation with HTLV-1-specific CTL response. Blood 111:5047–5053PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H (1977) Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 50:481–492PubMedGoogle Scholar
  25. 25.
    Yamamoto-Taguchi N, Satou Y, Miyazato P, Ohshima K, Nakagawa M, Katagiri K, Kinashi T, Matsuoka M (2013) HTLV-1 bZIP Factor Induces Inflammation through Labile Foxp3 Expression. Plos Pathogens 9:e1003630PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Yamano Y, Takenouchi N, Li HC, Tomaru U, Yao K, Grant CW, Maric DA, Jacobson S (2005) Virus-induced dysfunction of CD4 + CD25 + T cells in patients with HTLV-I-associated neuroimmunological disease. J Clin Invest 115:1361–1368PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Zhao T, Yasunaga J, Satou Y, Nakao M, Takahashi M, Fujii M, Matsuoka M (2009) Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-kappaB. Blood 113:2755–2764PubMedCrossRefGoogle Scholar
  28. 28.
    Zhao T, Satou Y, Sugata K, Miyazato P, Green PL, Imamura T, Matsuoka M (2011) HTLV-1 bZIP factor enhances TGF-beta signaling through p300 coactivator. Blood 118:1865–1876PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Zhao T, Matsuoka M (2012) HBZ and its roles in HTLV-1 oncogenesis. Front Microbiol 3:247PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  1. 1.College of Chemistry and Life SciencesZhejiang Normal UniversityJinhuaChina
  2. 2.Laboratory of Virus Control, Institute for Virus ResearchKyoto UniversityKyotoJapan
  3. 3.Priority Organization for Innovation and Excellence, Center for AIDS ResearchKumamoto UniversityKumamotoJapan

Personalised recommendations