Activation of nuclear factor of activated T cells by human T-Lymphotropic virus type 1 accessory protein p12I

被引:61
作者
Albrecht, B
D'Souza, CD
Wei, D
Tridandapani, S
Coggeshall, KM
Lairmore, MD
机构
[1] Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA
[2] Ohio State Univ, Dept Vet Biosci, Columbus, OH 43210 USA
[3] Ohio State Univ, Coll Med & Publ Hlth, Dept Internal Med, Columbus, OH 43210 USA
[4] Ohio State Univ, Arthur G James Canc Res Hosp & Solove Res Inst, Ctr Comprehens Canc, Columbus, OH 43210 USA
[5] Oklahoma Med Res Fdn, Immunobiol & Canc Res Program, Oklahoma City, OK 73104 USA
关键词
D O I
10.1128/JVI.76.7.3493-3501.2002
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Human T-lymphotropic virus type 1 (HTLV-1) is the agent of an aggressive malignancy of CD4(+) T lymphocytes, called adult T-cell lymphoma/leukemia, and is associated with numerous immune-mediated diseases. To establish infection, HTLV-1 must activate targeted T cells during early stages of infection. We recently demonstrated that the HTLV-1 accessory protein p12(I) is critical for persistent infection in vivo and for viral infectivity in quiescent primary lymphocytes, suggesting a role for p12(I) in lymphocyte activation. To test whether p12(I) modulates signaling pathways required for T-lymphocyte activation, we examined AP-1-, NT-kappaB-, and nuclear factor of activated T cells (NFAT)-driven reporter gene activity in p12(I)-expressing Jurkat T cells compared to vector-transfected control cells. HTLV-1 p12(I) specifically induced NFAT-mediated transcription approximately 20-fold in synergy with the Ras/mitogen-activated protein kinase pathway, but did not influence AP-1- or NF-kappaB-dependent gene expression. Inhibition of calcium-dependent signals by cyclosporin A, BAPTA-AM [glycine, N,N'-1,2-ethanedlylbis(oxy-2,1-phenylene)-bis-N-2-(acetyloxy)methoxy-2-oxoethyl]-[bis (acetyloxy)methyl ester], and a dominant negative mutant of NFAT2 abolished the p12(I)-mediated activation of NFAT-dependent transcription. In contrast, inhibition of phospholipase C-gamma and LAT (linker for activation of T cells) did not affect p12(I)-induced NFAT activity. Importantly, p12(I) functionally substituted for thapsigargin, which selectively depletes intracellular calcium stores. Our data are the first to demonstrate a role for HTLV-1 p12(I) in calcium-dependent activation of NFAT-mediated transcription in lymphoid cells. We propose a novel mechanism by which HTLV-1, a virus associated with lymphoproliferative disease, dysregulates common T-cell activation pathways critical for the virus to establish persistent infection.
引用
收藏
页码:3493 / 3501
页数:9
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