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.
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.
Pichler
Klemens
K
Institute of Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Kattan
Tarek
T
Gentzsch
Juliane
J
Kress
Andrea K
AK
Taylor
Graham P
GP
Bangham
Charles R M
CR
Grassmann
Ralph
R
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells / Q000821:virology; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000502:physiology*; D015490:HTLV-I Infections / Q000473:pathology*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D016328:NF-kappa B; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics*; D015854:Up-Regulation
D016356:Gene Products, tax; D016328:NF-kappa B; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9