title: HTLV-1 bZIP factor impairs cell-mediated immunity by suppressing production of Th1 cytokines.
abstract: Adult T-cell leukemia (ATL) patients and human T-cell leukemia virus-1 (HTLV-1) infected individuals succumb to opportunistic infections. Cell mediated immunity is impaired, yet the mechanism of this impairment has remained elusive. The HTLV-1 basic leucine zipper factor (HBZ) gene is encoded in the minus strand of the viral DNA and is constitutively expressed in infected cells and ATL cells. To test the hypothesis that HBZ contributes to HTLV-1-associated immunodeficiency, we challenged transgenic mice that express the HBZ gene in CD4 T cells (HBZ-Tg mice) with herpes simplex virus type 2 or Listeria monocytogenes, and evaluated cellular immunity to these pathogens. HBZ-Tg mice were more vulnerable to both infections than non-Tg mice. The acquired immune response phase was specifically suppressed, indicating that cellular immunity was impaired in HBZ-Tg mice. In particular, production of IFN-γ by CD4 T cells was suppressed in HBZ-Tg mice. HBZ suppressed transcription from the IFN-γ gene promoter in a CD4 T cell-intrinsic manner by inhibiting nuclear factor of activated T cells and the activator protein 1 signaling pathway. This study shows that HBZ inhibits CD4 T-cell responses by directly interfering with the host cell-signaling pathway, resulting in impaired cell-mediated immunity in vivo.
authors: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Japan.
authors: Kenji
authors: K
authors: Sugata
authors: Yorifumi
authors: Y
authors: Satou
authors: Jun-ichirou
authors: J
authors: Yasunaga
authors: Hideki
authors: H
authors: Hara
authors: Kouichi
authors: K
authors: Ohshima
authors: Atae
authors: A
authors: Utsunomiya
authors: Masao
authors: M
authors: Mitsuyama
authors: Masao
authors: M
authors: Matsuoka
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006561:Herpes Simplex / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018258:Herpesvirus 2, Human / Q000472:pathogenicity; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D008089:Listeria monocytogenes / Q000472:pathogenicity; D008088:Listeriosis / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012191:Retroviridae Proteins; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014764:Viral Proteins / Q000502:physiology*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D016207:Cytokines; C479751:HBZ protein, human T-cell leukemia virus type I; D012191:Retroviridae Proteins; D018808:Transcription Factor AP-1; D014764:Viral Proteins; D007371:Interferon-gamma