Strong induction of 4-1BB, a growth and survival promoting costimulatory receptor, in HTLV-1-infected cultured and patients' T cells by the viral Tax oncoprotein

Blood. 2008 May 1;111(9):4741-51. doi: 10.1182/blood-2007-10-115220. Epub 2008 Feb 14.


Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia, stimulates the growth of infected T cells in cultures and in nonleukemic patients. In the latter, HTLV-1 is found in long-term persisting T-cell clones. The persistence of normal T cells is controlled by the growth-stimulating and antiapoptotic functions of costimulatory receptors, while the growth-stimulating HTLV-1 functions are mediated by the viral oncoprotein Tax. Here we analyzed the impact of Tax on costimulatory receptors in T cells with repressible Tax and found that among these receptors 4-1BB (TNFRSF9/CD137/ILA) was induced most strongly. Up-regulated 4-1BB expression was a consistent feature of all HTLV-1-infected cell lines, whether patient-derived or in vitro transformed. Tax was sufficient to induce the expression of the endogenous 4-1BB gene in uninfected T cells, and it strongly activated (45-fold) the 4-1BB promoter via a single NF-kappaB site. The ligand of 4-1BB was also found on transformed T-cell lines, opening up the possibility of autostimulation. Moreover, 4-1BB expression in patients' lymphocytes ex vivo correlated with Tax expression, strongly suggesting Tax-mediated 4-1BB activation in vivo. Thus, 4-1BB up-regulation by Tax could contribute to growth, survival, and clonal expansion of the infected cells during persistence and disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Clone Cells / virology
  • Gene Expression Regulation*
  • Gene Products, tax / physiology*
  • HTLV-I Infections / pathology*
  • Human T-lymphotropic virus 1
  • Humans
  • NF-kappa B
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics*
  • Up-Regulation


  • Gene Products, tax
  • NF-kappa B
  • TNFRSF9 protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 9