Downregulation of proapoptotic Bim augments IL ‐2‐independent T‐cell transformation by human T‐cell leukemia virus type‐1 Tax

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.