Abstract
Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion–induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo.
Highlights
Adult T-cell leukemia (ATL) is a highly aggressive human leukemia characterized by the clonal proliferation of mature T cells and is initiated by an infection with human T-cell leukemia virus type 1 (HTLV-1) [1, 2]
We investigated the status of Bim protein in HTLV-1-transformed IL-2-independent T-cell lines and in T-cell lines that originated from ATL patients
We found that Tax attenuates the induction of Bim protein in the T-cell line CTLL-2 after IL-2 depletion, and that this reduction promotes the Tax-induced
Summary
Adult T-cell leukemia (ATL) is a highly aggressive human leukemia characterized by the clonal proliferation of mature T cells and is initiated by an infection with human T-cell leukemia virus type 1 (HTLV-1) [1, 2]. 3–5% of HTLV-1 infections develop into ATL, at an average age of 60 years [3]. Host immunity suppresses the outgrowth of HTLV-1-infected cells. Two events, deterioration of host immunity and emergence of a malignant clone with genetic and epigenetic alterations, overcome suppression against HTLV-1infected T cells, resulting in the development of ATL [4, 5]. HTLV-1 immortalizes primary human T cells in vitro, and subsequently some cells acquire an interleukin-2 (IL-2)-independent growth phenotype [6]. This HTLV-1induced immortalization and transformation event is essential for establishing a lifelong persistent infection. Tax is essential for HTLV-1-mediated IL-2-dependent immortalization of a 2014 The Authors.
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