TY - JOUR
T1 - Deregulated expression of CD40 ligand in HTLV-I infection
T2 - Distinct mechanisms of downregulation in HTLV-I-transformed cell lines and ATL patients
AU - Harhaj, Nicole S.
AU - Janic, Branislava
AU - Ramos, Juan C.
AU - Harrington, William J.
AU - Harhaj, Edward W.
N1 - Funding Information:
We thank Drs. Shao-Cong Sun (Penn State College of Medicine), Brian Wigdahl (Drexel University), Michiyuki Maeda (Kyoto University), Gutian Xiao (Rutgers University), Naoki Mori (Ryukyu University) and Masataka Nakamura (Tokyo Medical and Dental University) for reagents. We thank the NIH AIDS Research and Reference Program for cell lines. We thank V. Jurecic of the Molecular Analysis Core Facility at the University of Miami Miller School of Medicine for assistance with real-time PCR and J. Philips of the Flow Cytometry Core for assistance with flow cytometry. These studies were supported by a grant from the United States Public Health Service/National Institutes of Health (CA99926 to EWH).
PY - 2007/5/25
Y1 - 2007/5/25
N2 - HTLV-I infection is associated with the development of adult T cell leukemia (ATL) and the neuroinflammatory disease HAM/TSP. There are quantitative and qualitative differences in the antiviral cytotoxic T cell (CTL) response in ATL and HAM/TSP although the underlying mechanisms are unclear. Here, we demonstrate that the HTLV-I Tax trans-activating protein is a transcriptional activator of CD40 ligand (CD40L), a critical regulator of dendritic cell maturation and adaptive immunity. Tax activates CD40L expression via a cyclosporin A insensitive pathway that is also independent of NF-κB. Although Tax upregulates CD40L gene expression, CD40L expression is absent in Tax-expressing HTLV-I-transformed cell lines via an epigenetic mechanism involving methylation. T lymphocytes cultured ex vivo from ATL patients, but not HAM/TSP or normal controls, exhibit a potent block in the induction of CD40L, but not CD69. However, the CD40L gene is not silenced by methylation in ATL patients, thus CD40L is downregulated by distinct mechanisms in HTLV-I-transformed cell lines and ATL patients.
AB - HTLV-I infection is associated with the development of adult T cell leukemia (ATL) and the neuroinflammatory disease HAM/TSP. There are quantitative and qualitative differences in the antiviral cytotoxic T cell (CTL) response in ATL and HAM/TSP although the underlying mechanisms are unclear. Here, we demonstrate that the HTLV-I Tax trans-activating protein is a transcriptional activator of CD40 ligand (CD40L), a critical regulator of dendritic cell maturation and adaptive immunity. Tax activates CD40L expression via a cyclosporin A insensitive pathway that is also independent of NF-κB. Although Tax upregulates CD40L gene expression, CD40L expression is absent in Tax-expressing HTLV-I-transformed cell lines via an epigenetic mechanism involving methylation. T lymphocytes cultured ex vivo from ATL patients, but not HAM/TSP or normal controls, exhibit a potent block in the induction of CD40L, but not CD69. However, the CD40L gene is not silenced by methylation in ATL patients, thus CD40L is downregulated by distinct mechanisms in HTLV-I-transformed cell lines and ATL patients.
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U2 - 10.1016/j.virol.2006.12.020
DO - 10.1016/j.virol.2006.12.020
M3 - Article
C2 - 17258259
AN - SCOPUS:34247211117
SN - 0042-6822
VL - 362
SP - 99
EP - 108
JO - Virology
JF - Virology
IS - 1
ER -