title: Aberrant activation of the interleukin-2 autocrine loop through the nuclear factor of activated T cells by nonleukemogenic human T-cell leukemia virus type 2 but not by leukemogenic type 1 virus.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia. We found that HTLV-2 Tax2 protein stimulated reporter gene expression regulated by the interleukin (IL)-2 promoter through the nuclear factor of activated T cells (NFAT) in a human T-cell line (Jurkat). However, the activity of HTLV-1 Tax1 was minimal in this system. T-cell lines immortalized by HTLV-2 but not HTLV-1 constitutively exhibited activated NFAT in the nucleus and constitutively expressed IL-2 mRNA. Cyclosporine A, an inhibitor of NFAT activation, abrogated the induction of IL-2 mRNA in HTLV-2-immortalized T-cell lines and concomitantly inhibited cell growth. This growth inhibition was rescued by the addition of IL-2 to the culture. Furthermore, anti-IL-2 receptor antibodies significantly reduced the proliferation of HTLV-2-infected T-cell lines but not that of HTLV-1-infected cells. Our results suggest that Tax2 activates an IL-2 autocrine loop mediated through NFAT that supports the growth of HTLV-2-infected cells under low-IL-2 conditions. This mechanism would be especially important in vivo, where this autocrine mechanism establishes a nonleukemogenic life-long HTLV-2 infection. The results also suggest that differences in long-term cytokine production between HTLV-1 and HTLV-2 infection are another factor for the differences in pathogenesis.
authors.affiliation: Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Niigata 951-8510, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Niinuma
authors.forename: Masaya
authors.initials: M
authors.lastname: Higuchi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masayasu
authors.initials: M
authors.lastname: Oie
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Fumitake
authors.initials: F
authors.lastname: Gejyo
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Green
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujii
mesh_terms: D001483:Base Sequence; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D016356:Gene Products, tax / Q000235:genetics / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D015367:Human T-lymphotropic virus 2 / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000235:genetics*; D019169:Jurkat Cells; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D016572:Cyclosporine