The HTLV-I tax protein transcriptionally modulates OX40 antigen expression.
OX40 is a member of the TNF receptor family, expressed on activated T cells. It is the only costimulatory T cell molecule known to be specifically up-regulated in human T cell leukemia virus type-I (HTLV-I)-producing cells. In a T cell line, OX40 surface expression was shown to be induced by HTLV-I Tax alone. To understand molecular mechanisms of OX40 gene regulation and modulation by HTLV-I Tax, we have cloned the human OX40 gene and analyzed its 5'-flanking region. By reporter gene analysis with progressive 5' deletions from nucleotides -1259 to -64, we have defined a 157-bp DNA fragment as a minimal promoter for constitutive expression. In addition, we show that in the OX40+ cell line, Co, Tax is able to further increase OX40 surface expression. Up-regulation of OX40 promoter activity by Tax requires two upstream NF-kappaB sites, which are not active in the constitutive OX40 expression. Their deletion abrogates Tax responsiveness in reporter gene analysis. The site-directed mutagenesis of each NF-kappaB site demonstrates that cooperative NF-kappaB binding is a prerequisite for Tax-directed activity as neither site alone is sufficient for a full Tax responsiveness of the OX40 promoter. Upon Tax expression, both sites bind p65 and c-Rel. These data provide new insight into the direct regulation of OX40 by Tax and add to our understanding of the possible role of the OX40/OX40 ligand system in the proliferation of HTLV-I+ T cells.
Pankow
R
R
Departments of Pathology and Urology, University Hospital Benjamin Franklin, Free University Berlin, Germany.
Dürkop
H
H
Latza
U
U
Krause
H
H
Kunzendorf
U
U
Pohl
T
T
Bulfone-Paus
S
S
D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D003001:Cloning, Molecular; D016356:Gene Products, tax / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D014158:Transcription, Genetic / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology; D014407:Tumor Cells, Cultured; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism
D016356:Gene Products, tax; D016328:NF-kappa B; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7