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Activation of Nuclear Factor of Activated T Cells by Human T-Lymphotropic Virus Type 1 Accessory Protein p12^I

Björn Albrecht,¹ Celine D. D'Souza,^1, Wei Ding,¹ Susheela Tridandapani,^2, K. Mark Coggeshall,³ and Michael D. Lairmore^1,4*

Center for Retrovirus Research and Department of Veterinary Biosciences,¹ Department of Internal Medicine, College of Medicine and Public Health,² Comprehensive Cancer Center, The Arthur G. James Cancer Research Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio 43210,⁴ Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104³

Received 11 October 2001/ Accepted 27 December 2001

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-, NF-B-, 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-B-dependent gene expression. Inhibition of calcium-dependent signals by cyclosporin A, BAPTA-AM [glycine, N,N'-1,2-ethanediylbis(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- 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.

Present address: Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.

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