Affiliation:
1. Center for Retrovirus Research and Department of Veterinary Biosciences
2. Department of Internal Medicine, College of Medicine and Public Health
3. Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104
4. Comprehensive Cancer Center, The Arthur G. James Cancer Research Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio 43210
Abstract
ABSTRACT
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-κB-, 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-κB-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-γ 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.
Publisher
American Society for Microbiology
Subject
Virology,Insect Science,Immunology,Microbiology
Cited by
69 articles.
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