Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells.
Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T-cell receptor stimulation of LTR-Tax CD4(+) T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immortalization was accompanied by markedly increased expression of the antiapoptotic gene, mcl-1, previously implicated as important in T-cell survival. Immortalized cells exhibited a CD4(+)CD25(+)CD3(-) phenotype commonly observed in ATL. Engraftment of activated LTR-Tax CD4(+) T cells into NOD/Shi-scid/IL-2Rγ null mice resulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax(+), CD4(+) lymphocytes. We suggest that immune activation of infected CD4(+) T cells plays an important role in the induction of Tax expression, T-cell proliferation, and pathogenesis of ATL in HTLV-1-infected individuals.
Swaims
Alison Y
AY
Child Health Institute of New Jersey, University of Medicine and Dentistry of New Jersey (UMDNJ), Robert Wood Johnson Medical School (RWJMS), New Brunswick, NJ 08901, USA.
Khani
Francesca
F
Zhang
Yingyu
Y
Roberts
Arthur I
AI
Devadas
Satish
S
Shi
Yufang
Y
Rabson
Arnold B
AB
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D015870:Gene Expression; D016356:Gene Products, tax / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D016207:Cytokines; D016356:Gene Products, tax