HTLV-1 bZIP Factor Induces T-Cell Lymphoma and Systemic Inflammation In Vivo

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.

Host Immune System Abnormalities Among Patients with Human T-Lymphotropic Virus Type 1 (HTLV-1) - Associated Disorders

“…Importantly, Toulza et al (2008) demonstrated that the rate of CTL-mediated lysis was negatively correlated with the number of HTLV-1-Tax -CD4 + Foxp3 + cells, but not with the number of Tax + CD4 + Foxp3 + cells, suggesting that HTLV-1-infected Treg cells lose their regulatory function, while HTLV-1-uninfected Treg cells contribute substantially to immune control of HTLV-1 infection. Additionally, functional impairment of CD4 + Foxp3 + Treg cells was observed in mice that were transgenic mice for the HTLV-1 bZIP factor (HBZ) gene, which encodes the minus strand of HTLV-1 (Satou et al, 2011). These findings support the hypothesis that HTLV-1 may be one of the exogenous retrovirus genes responsible for immune dysregulation through interference of CD4 + CD25 + Treg cell function.…”

Hypomethylation of the Treg-Specific Demethylated Region in FOXP3 Is a Hallmark of the Regulatory T-cell Subtype in Adult T-cell Leukemia

“…þ T cells increased, and these HBZ-induced Tregs had unstable FOXP3 expression, impaired function, and methylated TSDRs (36). However, primary ATL cells were not assessed in these experiments.…”

“…HTLV-1-encoded tax and HBZ not related to the hypomethylation of TSDR It was reported that the HTLV-1-associated molecules tax and HBZ affected the expression of FOXP3 (35,36). To clarify the relationship between FOXP3 expression and these molecules, we analyzed mRNA expression.…”

Mystery of Human T-cell Leukemia Virus Type 1: Commentary on Two Viral Genes, Tax and HBZ

“…HBZ was then reported to promote T cell proliferation in culture and was shown to be oncogenic in transgenic mice [7]. HBZ appeared to function in the opposite manner to Tax during HTLV-1 expression, but in the same manner during cell proliferation.…”