Foxp3-dependent transformation of human primary CD4+ T lymphocytes by the retroviral protein tax

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• 作者：Li Chen^a ; ^b ; ¹ ; Dan Liu^b ; ¹ ; Yang Zhang^b ; Huan Zhang^b ; Hua Cheng^b ; ^c ; ^d ; ^e ; ^{hcheng@ihv.umaryland.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HTLV tax ; Foxp3 ; Stat3 ; NF-魏B ; Transformation ; Autophagy
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2015
• 出版时间：23 October 2015
• 年：2015
• 卷：466
• 期：3
• 页码：523-529
• 全文大小：1914 K

文摘

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.