Background:  Human T cell leukemia virus type I (HTLV-I) induces a neoplastic disease, adult T cell leukemia, and inflammatory diseases, including HTLV-I-associated myelopathy/tropical spastic paraparesis. HTLV-I encodes regulatory and accessory genes, which induce proliferation of infected cells. Among them, the tax gene is thought to play an important role in oncogenesis by HTLV-I. However, the tax gene expression is frequently lost in adult T cell leukemia cells. HTLV-I bZIP factor (HBZ) gene is encoded by the minus strand of provirus, which is constantly expressed in adult T cell leukemia cells. Our previous study demonstrated that HBZ promoted proliferation of adult T cell leukemia cells. In this study, we analyzed effects of HBZ expression in the transgenic mice

Methods:  In the transgenic mice, HBZ gene was expressed under control of the promoter and enhancer of mouse CD4 gene. Surface markers of lymphocytes were analyzed by a flow cytometry.

Results:  In HBZ-transgenic (HBZ-Tg) mice, the number of CD4⁺ T cells increased according to aging. In particular, memory CD4⁺ T cells (CD44^high and CD62L^low) was predominant. In strain 12, in which HBZ expression was high, we observed dermatitis. The histological analyses revealed the infiltration of lymphocytes into epidermis and dermis. Immunohistochemical studies showed that infiltrating cells were CD3, CD4⁺ T cells. In addition, such infiltration of T cells was also observed in alveolar septum of the transgenic mice. As mechanisms, we found that CD4⁺ T cells of HBZ-Tg mice expressed increased level of LFA-1, and their adhesion to ICAM-1 was enhanced. In HTLV-I carriers, similar infiltration of infected CD4⁺ T cells was observed in the skin and lung, suggesting that HBZ is responsible for this phenomenon. Importantly, we observed developments of T cell lymphomas in 13 of 36 HBZ-Tg mice (34%), while only 2 cases were found in 27 non-transgenic littermates (7.4%). Immunohistochemical analyses showed that T cell lymphoma was CD4⁺, and expressed HBZ gene. One tumor of HBZ-Tg mouse could be transplanted into SCID mice, indicating the malignant phenotype of this tumor.

Conclusions:  This study demonstrates that HBZ gene is oncogenic in the transgenic mice. Considering that only HBZ expression was maintained in adult T cell leukemia cells, HBZ plays a critical role in the leukemogenesis of adult T cell leukemia. In addition, infiltrative phenotype conferred by HBZ expression suggests another role in the pathogenesis in HTLV-I-associated diseases like HTLV-I-associated myelopathy/tropical spastic paraparesis.