Human T cell leukemia virus type I Tax activates CD40 gene expression via the NF-kappa B pathway

Edward W. Harhaj, Nicole S. Harhaj, Christian Grant, Kate Mostoller, Timothy Alefantis, Shao Cong Sun, Brian Wigdahl

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24 Scopus citations

Abstract

The human T cell leukemia virus type I (HTLV-I) is an oncogenic retrovirus that is etiologically linked to the genesis of adult T cell leukemia (ATL) as well as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Emerging evidence suggests that the pathogenicity of HTLV-I involves deregulated activation of immune cells, especially T lymphocytes, although the underlying mechanism remains unclear. In this study, we demonstrate that HTLV-I Tax induces the aberrant expression of CD40, a member of the tumor necrosis factor receptor (TNFR) family that plays an important role in lymphocyte activation and differentiation. In a panel of HTLV-I-transformed T cell lines analyzed, CD40 expression was highly elevated compared to HTLV-I-negative T cells. Using Tax mutants and a genetically manipulated T cell system, we demonstrated that Tax-induced CD40 expression required the NF-κB signaling pathway. In addition, ligation of CD40 on T cells with recombinant CD40L elicited NF-κB activation, suggesting that the CD40 pathway is intact and may participate in a positive regulatory loop in T cells. CD40 ligation strongly synergized with Tax to activate NF-κB, suggesting that CD40 signals may costimulate Tax-mediated NF-κB activation, particularly when Tax is expressed at low levels. Collectively, these results indicate that CD40 is a novel Tax-regulated gene, and the regulation of CD40 by Tax may play a role in cellular activation and HTLV-I-induced disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)145-158
Number of pages14
JournalVirology
Volume333
Issue number1
DOIs
StatePublished - Mar 1 2005

All Science Journal Classification (ASJC) codes

  • Virology

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    Harhaj, E. W., Harhaj, N. S., Grant, C., Mostoller, K., Alefantis, T., Sun, S. C., & Wigdahl, B. (2005). Human T cell leukemia virus type I Tax activates CD40 gene expression via the NF-kappa B pathway. Virology, 333(1), 145-158. https://doi.org/10.1016/j.virol.2004.12.008