title: Foxp3-dependent transformation of human primary CD4+ T lymphocytes by the retroviral protein tax.
abstract: 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.
authors.affiliation: Pharmacy College, Fujian University of Traditional Chinese Medicine, Fuzhou, China; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Departments of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: hcheng@ihv.umaryland.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Cheng
mesh_terms: D001343:Autophagy / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology* / Q000821:virology*; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral / Q000276:immunology / Q000502:physiology*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000502:physiology*; D016356:Gene Products, tax / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity / Q000502:physiology; D015367:Human T-lymphotropic virus 2 / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000502:physiology / Q000821:virology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016356:Gene Products, tax; C514970:tax protein, Human T-lymphotrophic virus 1; C514971:tax protein, Human T-lymphotrophic virus 2; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Autophagy; Foxp3; HTLV tax; NF-κB; Stat3; Transformation