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Journal of Virology, September 2005, p. 11925-11934, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11925-11934.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Akiko Niinuma,^1,2, Masaya Higuchi,^1, Masahiko Takahashi,¹ Masayasu Oie,¹ Yuetsu Tanaka,³ Fumitake Gejyo,² Nobuyuki Tanaka,⁴ Kazuo Sugamura,⁴ Li Xie,⁵ Patrick L. Green,⁵ and Masahiro Fujii^1*

Division of Virology,¹ Division of Clinical Infection Control and Prevention, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Niigata, Japan,² Department of Infectious Disease and Immunology, Okinawa-Asia Research Center of Medical Science, Faculty of Medicine, University of the Ryukyus, Okinawa,³ Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan,⁴ Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio⁵

Received 28 December 2004/ Accepted 3 June 2005

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.

The first two authors contributed equally to this study.

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