title: 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 (T(reg)). Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for T(reg) 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+ T(reg) cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased T(reg) cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ T(reg) 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 T(reg) cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases.
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Yorifumi
authors.initials: Y
authors.lastname: Satou
authors.forename: Jun-Ichirou
authors.initials: J
authors.lastname: Yasunaga
authors.forename: Tiejun
authors.initials: T
authors.lastname: Zhao
authors.forename: Mika
authors.initials: M
authors.lastname: Yoshida
authors.forename: Paola
authors.initials: P
authors.lastname: Miyazato
authors.forename: Ken
authors.initials: K
authors.lastname: Takai
authors.forename: Kei
authors.initials: K
authors.lastname: Shimizu
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Green
authors.forename: Naganari
authors.initials: N
authors.lastname: Ohkura
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000328:Adult; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002472:Cell Transformation, Viral / Q000235:genetics / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D015490:HTLV-I Infections / Q000276:immunology / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000821:virology*; D016399:Lymphoma, T-Cell / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors