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. I n 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 m odulation by HTLV-I Tax, we have cloned the human OX40 gene and analyzed it s 5'-flanking region. By reporter gene analysis with progressive 5' deletio ns from nucleotides -1259 to -64, me have defined a 157-bp DNA fragment as a minimal promoter for constitutive expression. In addition, we show that i n the OX40(+) cell line, Co, Tax is able to further increase OX40 surface e xpression. Up-regulation of OX40 promoter activity by Tax requires two upst ream NF-kappa B sites, which are not active in the constitutive OX40 expres sion. Their deletion abrogates Tax responsiveness in reporter gene analysis . The site-directed mutagenesis of each NF-kappa B Site demonstrates that c ooperative NF-kappa B binding is a prerequisite for Tax-directed activity a s neither site alone is sufficient for a full Tax responsiveness of the OX4 0 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 ou r understanding of the possible role of the OX40/OX40 ligand system in the proliferation of HTLV-I+ T cells.