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

PLoS Pathogens

Patrick L. Green¹  Naganari Ohkura²  Shimon Sakaguchi²  Masahiro Ono²  Tomoyuki Yamaguchi²  Koichi Ohshima³  Kei Shimizu³  Yorifumi Satou⁴  Ken Takai⁴  Jun-ichirou Yasunaga⁴  Tiejun Zhao⁴  Mika Yoshida⁴  Paola Miyazato⁴  Masao Matsuoka⁴ 

[1] Center for Retrovirus Research and Departments of Veterinary Biosciences and Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America;Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan;Department of Pathology, Kurume University School of Medicine, Kurume, Japan;Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan

关键词: T cells;    Regulatory T cells;    HTLV-1;    Flow cytometry;    Lymphomas;    Forkhead box;    Immunoprecipitation;    Cell staining;   

DOI  :  10.1371/journal.ppat.1001274

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY