Human T cell leukemia virus type I Tax activates CD40 gene expression via the NF-kappa B pathway.
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-kappaB signaling pathway. In addition, ligation of CD40 on T cells with recombinant CD40L elicited NF-kappaB 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-kappaB, suggesting that CD40 signals may costimulate Tax-mediated NF-kappaB 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.
Harhaj
Edward W
EW
Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami School of Medicine, Miami, FL 33136, USA. eharhaj@med.miami.edu
Harhaj
Nicole S
NS
Grant
Christian
C
Mostoller
Kate
K
Alefantis
Timothy
T
Sun
Shao-Cong
SC
Wigdahl
Brian
B
D019013:CD40 Antigens / Q000096:biosynthesis*; D002460:Cell Line; D016356:Gene Products, tax / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D019013:CD40 Antigens; D016356:Gene Products, tax; D016328:NF-kappa B