Deregulated expression of CD40 ligand in HTLV-I infection: Distinct mechanisms of downregulation in HTLV-I-transformed cell lines and ATL patients

Nicole S. Harhaj, Branislava Janic, Juan Carlos Ramos, William J. Harrington, Edward W. Harhaj

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)99-108
Number of pages10
JournalVirology
Volume362
Issue number1
DOIs
StatePublished - May 25 2007

Fingerprint

HTLV-I Infections
Adult T Cell Leukemia Lymphoma
CD40 Ligand
Transformed Cell Line
Human T-lymphotropic virus 1
Down-Regulation
Methylation
T-Lymphocytes
Adaptive Immunity
Epigenomics
Dendritic Cells
Cyclosporine
Antiviral Agents
Up-Regulation
Gene Expression

Keywords

  • ATL
  • CD40L
  • Gene expression
  • HAM/TSP
  • HTLV-I
  • Methylation
  • NF-κB
  • NFAT
  • Tax

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

Cite this

Deregulated expression of CD40 ligand in HTLV-I infection : Distinct mechanisms of downregulation in HTLV-I-transformed cell lines and ATL patients. / Harhaj, Nicole S.; Janic, Branislava; Carlos Ramos, Juan; Harrington, William J.; Harhaj, Edward W.

In: Virology, Vol. 362, No. 1, 25.05.2007, p. 99-108.

Research output: Contribution to journalArticle

Harhaj, Nicole S. ; Janic, Branislava ; Carlos Ramos, Juan ; Harrington, William J. ; Harhaj, Edward W. / Deregulated expression of CD40 ligand in HTLV-I infection : Distinct mechanisms of downregulation in HTLV-I-transformed cell lines and ATL patients. In: Virology. 2007 ; Vol. 362, No. 1. pp. 99-108.
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