IL-2/IL-2 Receptor Pathway Plays a Crucial Role in the Growth and Malignant Transformation of HTLV-1-Infected T Cells to Develop Adult T-Cell Leukemia

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  • 前田, 道之
    Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University
  • 安永, 純一朗
    Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University
  • 清水, 章
    Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University･Center for AIDS Research, School of Medicine, Kumamoto University
  • 松岡, 雅雄
    Laboratory of Infection and Prevention, Institute for Frontier Life and Medical Sciences, Kyoto University･Department of Clinical Laboratory Sciences, Tenri Health Care University
  • Yasunaga, Jun Ichirou
    Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University･Institute for Advancement for Clinical and Translational Science, Kyoto University Hospital, Kyoto University
  • Usami, Kazumasa
    Taigenkai Hospital
  • Shimizu, Akira
    Institute for Advancement for Clinical and Translational Science, Kyoto University Hospital, Kyoto University
  • Matsuoka, Masao
    Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University･Department of Hematology, School of Medicine, Kumamoto University

抄録

T cells infected with human T-cell leukemia virus type 1 (HTLV-1) transform into malignant/leukemic cells and develop adult T-cell leukemia (ATL) after a long latency period. The tax (transactivator from the X-gene region) and HBZ (HTLV-1 bZIP factor) genes of HTLV-1 play crucial roles in the development of ATL. The process and mechanism by which HTLV-1-infected T cells acquire malignancy and develop ATL remain to be elucidated. Constitutive expression of interleukin-2 (IL-2) receptor α-chain (IL-2Rα/CD25), induced by the tax and HBZ genes of HTLV-1, on ATL cells implicates the involvement of IL-2/IL-2R pathway in the growth and development of ATL cells in vivo. However, the leukemic cells in the majority of ATL patients appeared unresponsive to IL-2, raising controversies on the role of this pathway for the growth of ATL cells in vivo. Here, we report the establishment of 32 IL-2-dependent T-cell lines infected with HTLV-1 from 26 ATL patients, including eight leukemic cell lines derived from five ATL patients, while no T-cell lines were established without IL-2. We have shown that the IL-2-dependent ATL cell lines evolved into IL-2-independent/-unresponsive growth phase, resembling ATL cells in vivo. Moreover, the IL-2-dependent non-leukemic T-cell lines infected with HTLV-1 acquired IL-2-independency and turned into tumor-producing cancer cells as with the ATL cell lines. HTLV-1-infected T cells in vivo could survive and proliferate depending on IL-2 that was produced in vivo by the HTLV-1-infected T cells of ATL patients and patients with HTLV-1-associated diseases and, acts as a physiological molecule to regulate T-cell growth. These results suggest that ATL cells develop among the HTLV-1-infected T cells growing dependently on IL-2 and that most of the circulating ATL cells progressed to become less responsive to IL-2, acquiring the ability to proliferate without IL-2.

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