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: Akiko Niinuma, Masaya Higuchi, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Fumitake Gejyo, Nobuyuki Tanaka, Kazuo Sugamura, Li Xie, Patrick L Green, Masahiro Fujii
• Journal: Journal of virology (J Virol) Vol. 79 Issue 18 Pg. 11925-34 (Sep 2005) ISSN: 0022-538X [Print] United States
• PMID: 16140768 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA-Binding Proteins
• Gene Products, tax
• Immunosuppressive Agents
• Interleukin-2
• NFATC Transcription Factors
• Nuclear Proteins
• RNA, Messenger
• Transcription Factors
• Cyclosporine

Topics

• Base Sequence
• Cyclosporine (pharmacology)
• DNA-Binding Proteins (metabolism)
• Gene Expression
• Gene Products, tax (genetics, immunology)
• Human T-lymphotropic virus 1 (genetics, immunology, pathogenicity)
• Human T-lymphotropic virus 2 (genetics, immunology, pathogenicity)
• Humans
• Immunosuppressive Agents (pharmacology)
• Interleukin-2 (genetics)
• Jurkat Cells
• NFATC Transcription Factors
• Nuclear Proteins (metabolism)
• Promoter Regions, Genetic
• RNA, Messenger (genetics)
• T-Lymphocytes (immunology, virology)
• Transcription Factors (metabolism)