Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL), and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, resemble CD25+CD4+ regulatory T cells (Treg). Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for Treg cells. HTLV-1 encodes an antisense transcript, HTLV-1 bZIP factor (HBZ), which is expressed in all ATL cases. In this study, we show that transgenic expression of HBZ in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice, resembling diseases observed in HTLV-1 infected individuals. In HBZ-transgenic mice, CD4+Foxp3+ Treg cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased Treg cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ Treg cells in HBZ transgenic mice were functionally impaired while their proliferation was enhanced. HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of Treg cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus associated with human diseases including adult T-cell leukemia (ATL) [1,2] and HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP)[3,4]
We show that transgenic expression of HTLV-1 bZIP factor (HBZ) increases Foxp3+ Treg cells and effector/memory T cells, leading to development of T-cell lymphomas and systemic inflammatory diseases
Human T-cell leukemia virus type 1 (HTLV-1) is the first retrovirus that is associated with human diseases including an aggressive leukemia derived from CD4+ T cells, adult Tcell leukemia (ATL), and chronic inflammatory diseases of the central nervous system, lung, or skin
Summary
Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus associated with human diseases including adult T-cell leukemia (ATL) [1,2] and HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP)[3,4]. HTLV-1 induces the proliferation of infected CD4+ T cells to increase further transmission [7]. It has been reported that APOBEC3G generates nonsense mutations in all HTLV-1 genes except HBZ [14], suggesting that the HBZ gene is indispensable for the growth and/ or survival of ATL cells and HTLV-1 infected cells. The HBZ gene product promotes the proliferation of ATL cells [13,15]. HBZ mRNA expression in HAM/TSP patients was well correlated with disease severity [16]. These findings suggest that HBZ has a critical role in the development of ATL and HAM/
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