HTLV-2 Tax immortalizes human CD4+ memory T lymphocytes by oncogenic activation and dysregulation of autophagy.
Human T cell leukemia virus type 1 and type 2 (HTLV-1 and -2) are two closely related retroviruses with the former causing adult T cell leukemia. HTLV-2 infection is prevalent among intravenous drug users, and the viral genome encodes the viral transactivator Tax, which is highly homologous to the transforming protein Tax from HTLV-1. However, the link between HTLV-2 infection and leukemia has not been established. In the present study, we evaluated the activity of HTLV-2 Tax in promoting aberrant proliferation of human CD4 T lymphocytes. Tax2 efficiently immortalized CD4(+) memory T lymphocytes with a CD3/TCRαβ/CD4/CD25/CD45RO/CD69 immunophenotype, promoted constitutive activation of PI3K/Akt, IκB kinase/NF-κB, mitogen-activated protein kinase, and STAT3, and it also increased the level of Mcl-1. Disruption of these oncogenic pathways led to growth retardation and apoptotic cell death of the Tax2-established T cell lines. We further found that Tax2 induced autophagy by interacting with the autophagy molecule complex containing Beclin1 and PI3K class III to form the LC3(+) autophagosome. Tax2-mediated autophagy promoted survival and proliferation of the immortalized T cells. The present study demonstrated the oncogenic properties of Tax2 in human T cells and also implicated Tax2 in serving as a molecular tool to generate distinct T cell subtype lines.
Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Tong
T
Ren
Wen
W
Dong
Yoshinori
Y
Takahashi
Di
D
Xiang
Yunsheng
Y
Yuan
Xin
X
Liu
Thomas P
TP
Loughran
Shao-Cong
SC
Sun
Hong-Gang
HG
Wang
Hua
H
Cheng
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002472:Cell Transformation, Viral; D004789:Enzyme Activation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D015491:HTLV-II Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015367:Human T-lymphotropic virus 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007156:Immunologic Memory; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D016356:Gene Products, tax; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C514971:tax protein, Human T-lymphotrophic virus 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases