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.

Michiyuki Maeda,Paola Miyazato,Kazumasa Usami,Masao Matsuoka,Hiroshi Masutani,Junko Tanabe-Shibuya,Akira Shimizu,Jun-Ichirou Yasunaga

doi:10.3389/fmicb.2020.00356

Abstract

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.

Highlights

A unique T-cell leukemia endemic to the southwestern district of Japan was described in the early 1970s and was reported as adult T-cell leukemia (ATL) in 1977 (Yodoi et al, 1974; Uchiyama et al, 1977)
Thirty-two IL-2-dependent T-cell lines infected with human T-cell leukemia virus type 1 (HTLV-1) were established from the peripheral blood mononuclear cells (PBMC) of 26 ATL patients in the presence of IL-2
Eight IL-2-dependent leukemic cell lines, which have the same TCR β-chain (TCRβ) chain gene rearrangement and HTLV-1 provirus integration site as the leukemic cells in the patient, were established from five ATL patients (Figures 1A–E). Four of these leukemic cell lines were established from a patient with chronic ATL who had been initially diagnosed as suffering from erythroderma (ED) and was infected with HTLV-1 during the clinical course over 3 years

Summary

Introduction

A unique T-cell leukemia endemic to the southwestern district of Japan was described in the early 1970s and was reported as ATL in 1977 (Yodoi et al, 1974; Uchiyama et al, 1977). A retrovirus was detected in a T-cell line derived from a Japanese patient with ATL. The retrovirus infection was detected in all patients clinically suspected or diagnosed with ATL and some healthy individuals by using this cell line in 1981 (Hinuma et al, 1981; Miyoshi et al, 1981a; Yoshida et al, 1982). In ATL patients and healthy HTLV-1 carriers, polyclonal T cells were infected with HTLV-1 (Etoh et al, 1997; Gillet et al, 2011)

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