Influence of human T-cell leukemia virus type I tax and rex on interleukin-2 gene expression

Abstract

The X region of human T-cell leukemia virus type I (HTLV-I) encodes two proteins that regulate viral gene expression. The tax protein is the product of the transactivator gene and has been shown to up-regulate the expression of some cellular genes controlling T-cell replication, including that of the interleukin-2 (IL-2) T-cell growth hormone and the a chain of its receptor (IL-2R). Several studies have shown that tax transactivation of the IL-2R a-chain promoter is mediated by binding sites for the transcriptional activator NF-KB, and this mechanism has also been implicated in the tax activation of IL-2 promoter activity. The rex gene product of HTLV-I regulates viral protein production by influencing mRNA expression and has been implicated in the stabilization of IL-2R a-chain mRNA. In the present studies, the ability of the tax and rex proteins to transactivate IL-2 gene expression has been reinvestigated. The ability of the tax protein to transactivate IL-2 promoter activity appears, at least in part, to be mediated by the recognition sequence for a DNA-binding complex known as CD28RC. Consistent with this hypothesis is the observation that tax-mediated activation of IL-2 gene expression is resistant to the immunosuppressive affects of cyclosporin A, a property postulated for the CD28RC binding complex. Unexpectedly, this tax-mediated up-regulation of IL-2 expression is synergized by the presence of the rex protein. These findings demonstrate that transactivation of IL-2 gene expression by tax is augmented by mechanisms distinct from NF-cB and raise the possibility that rex, as well as tax, contributes to the oncogenic capability of HTLV-I by altering the expression of the IL-2 gene in T cells infected with this retrovirus. * Corresponding author. pression of the IL-2 gene is tightly controlled, and activation of this gene product requires multiple signals. At the transcriptional level, the expression of the human IL-2 gene is activated by several transcription factors (for a review, see reference 46). One of these is the inducible NFAT-1 protein which is necessary but not sufficient for IL-2 gene activity through the T-cell receptor. The abrogation of IL-2 promoter activity by the immunosuppressant cyclosporin A has been shown to be due to a block in the activity of this transcription factor (12). Other proteins, such as NF-KB, AP-1 (from c-fos and c-jun), and octamer binding proteins, are also reported to be involved but not sufficient for IL-2 gene activation. The studies presented here show that transactivation of the IL-2 promoter by tax is mediated, at least in part, by the binding site for the CD28RC complex which is activated by CD28 stimulation of T cells (13). In addition, endogenous IL-2 production and IL-2 promoter activity are shown to be resistant to the immunosuppressive effects of cyclosporin A in the presence of tax. This response appears to be synergized by the presence of rex. These data support the hypothesis that IL-2 gene activation in the presence of HTLV-I proteins may be via a pathway...

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