Foxp3-dependent transformation of human primary CD4+ T lymphocytes by the retroviral protein tax.
Foxp3-dependent transformation of human primary CD4+ T lymphocytes by the retroviral protein tax.
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DOI：
10.1016/j.bbrc.2015.09.063
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发表时间：
2015-10-23
影响因子：
3.1
通讯作者：
Cheng H
中科院分区：
文献类型：
--
作者：
Chen L;Liu D;Zhang Y;Zhang H;Cheng H
人T细胞白血病病毒1型和2型（HTLV-1和-2）的逆转录病毒Tax蛋白是高度同源的病毒反式激活因子。这两种病毒蛋白都可以使人原代CD 4+记忆T细胞永生化，但单独表达时，它们很少转化T细胞。在本研究中，我们发现Tax蛋白显示出使具有CTLA-4和GITR特征性表达的人CD 4 + Foxp 3 + T细胞永生化的差异能力。因为表皮生长因子受体（EGFR）在CD 4 + Foxp 3 + T细胞亚群中表达和活化，我们将活化的EGFR引入Tax永生化的CD 4 + Foxp 3 + T细胞中。我们观察到，这些修饰的细胞生长独立于外源性IL-2，与T细胞转化表型。在Tax永生化的CD 4 + Foxp 3- T细胞中，Foxp 3的异位表达是Tax转化T细胞的先决条件。因此，用EGFR的选择性抑制剂厄洛替尼处理转化的T细胞诱导溶酶体中EGFR的降解，从而引起T细胞生长抑制。此外，我们将自噬鉴定为转化T细胞的关键细胞存活途径。沉默关键的自噬分子，包括Beclin 1，Atg 5和PI 3激酶III类（PI 3 KC 3），导致T细胞生长的严重损害。因此，我们的数据揭示了Foxp 3在T细胞转化中先前未被识别的作用，为CD 4 + Foxp 3 + T细胞的HTLV-1转化提供了分子基础。
The retroviral Tax proteins of human T cell leukemia virus type 1 and 2 (HTLV-1 and -2) are highly homologous viral transactivators. Both viral proteins can immortalize human primary CD4+ memory T cells, but when expressed alone they rarely transform T cells. In the present study, we found that the Tax proteins displayed a differential ability to immortalize human CD4+Foxp3+ T cells with characteristic expression of CTLA-4 and GITR. Because epidermal growth factor receptor (EGFR) was reportedly expressed and activated in a subset of CD4+Foxp3+ T cells, we introduced an activated EGFR into Tax-immortalized CD4+Foxp3+ T cells. We observed that these modified cells were grown independently of exogenous IL-2, correlating with a T cell transformation phenotype. In Tax-immortalized CD4+Foxp3- T cells, ectopic expression of Foxp3 was a prerequisite for Tax transformation of T cells. Accordingly, treatment of the transformed T cells with erlotinib, a selective inhibitor of EGFR, induced degradation of EGFR in lysosome, consequently causing T cell growth inhibition. Further, we identified autophagy as a crucial cellular survival pathway for the transformed T cells. Silencing key autophagy molecules including Beclin1, Atg5 and PI3 kinase class III (PI3KC3) resulted in drastic impairment of T cell growth. Our data, therefore, unveiled a previously unidentified role of Foxp3 in T cell transformation, providing a molecular basis for HTLV-1 transformation of CD4+Foxp3+ T cells.