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PTD-hFOXP3 protein acts as an immune regulator to convert human CD4+CD25 T cells to regulatory T-like cells

Authors

  • Xia Liu,

    1. Department of Immunology, School of Medical Science and Laboratory Medicine, Key Discipline of Clinical Medical Science of Jiangsu Province, Jiangsu University, Zhenjiang 212013, Jiangsu, China
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  • Xun Xu,

    1. Department of Immunology, School of Medical Science and Laboratory Medicine, Key Discipline of Clinical Medical Science of Jiangsu Province, Jiangsu University, Zhenjiang 212013, Jiangsu, China
    2. Center for Biomaterial Development and Berlin-Brandenburg, Centre for Regenerative Therapies, Institute of Polymer Research, Helmholtz-Zentrum Geesthacht, Teltow 14513, Germany
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  • Xin Lin,

    1. Department of Immunology, School of Medical Science and Laboratory Medicine, Key Discipline of Clinical Medical Science of Jiangsu Province, Jiangsu University, Zhenjiang 212013, Jiangsu, China
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  • Yuxiang Tian,

    1. Department of Immunology, School of Medical Science and Laboratory Medicine, Key Discipline of Clinical Medical Science of Jiangsu Province, Jiangsu University, Zhenjiang 212013, Jiangsu, China
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  • Baoju Ji,

    1. Department of Immunology, School of Medical Science and Laboratory Medicine, Key Discipline of Clinical Medical Science of Jiangsu Province, Jiangsu University, Zhenjiang 212013, Jiangsu, China
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  • Sheng Xia,

    1. Department of Immunology, School of Medical Science and Laboratory Medicine, Key Discipline of Clinical Medical Science of Jiangsu Province, Jiangsu University, Zhenjiang 212013, Jiangsu, China
    2. Department of Clinical Laboratory, Zhenjiang Key Laboratory of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China
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  • Sanrong Xu,

    1. Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China
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  • Qing Yin,

    1. Department of Clinical Laboratory, Zhenjiang Key Laboratory of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China
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  • Miaomiao Zhang,

    1. Department of Immunology, School of Medical Science and Laboratory Medicine, Key Discipline of Clinical Medical Science of Jiangsu Province, Jiangsu University, Zhenjiang 212013, Jiangsu, China
    2. Department of Clinical Laboratory, Zhenjiang Key Laboratory of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China
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  • Zhijun Jiao,

    1. Department of Clinical Laboratory, Zhenjiang Key Laboratory of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China
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  • Shengjun Wang,

    1. Department of Immunology, School of Medical Science and Laboratory Medicine, Key Discipline of Clinical Medical Science of Jiangsu Province, Jiangsu University, Zhenjiang 212013, Jiangsu, China
    2. Department of Clinical Laboratory, Zhenjiang Key Laboratory of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China
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  • Huaxi Xu,

    1. Department of Immunology, School of Medical Science and Laboratory Medicine, Key Discipline of Clinical Medical Science of Jiangsu Province, Jiangsu University, Zhenjiang 212013, Jiangsu, China
    2. Department of Clinical Laboratory, Zhenjiang Key Laboratory of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China
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  • Qixiang Shao

    Corresponding author
    1. Department of Immunology, School of Medical Science and Laboratory Medicine, Key Discipline of Clinical Medical Science of Jiangsu Province, Jiangsu University, Zhenjiang 212013, Jiangsu, China
    2. Department of Clinical Laboratory, Zhenjiang Key Laboratory of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China
    • Department of Immunology, School of Medical Science and Laboratory Medicine, Key Discipline of Clinical Medical Science of Jiangsu Province, Jiangsu University, Zhenjiang 212013, Jiangsu, China.
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  • Xia Liu, Xun Xu, and Xin Lin contributed equally to this work.

Abstract

Regulatory T cells (Tregs) are critical for maintaining self-tolerance and homeostasis, and have potential application in clinical disease therapy, such as autoimmune diseases and transplant rejection, but their numbers are limited. FOXP3 is a key transcription factor controlling Tregs development and function. Although transfection of CD4+CD25 lymphocytes with the FOXP3 gene can convert them to Treg-like cells, there is the risk of insertional mutagenesis and thus an alternative to genetic intervention is sought. The protein transduction domain (PTD) from the HIV transactivator of transcription is a useful tool to deliver protein to the cytoplasm and nucleus. In this study, we generated a fusion protein linking the human FOXP3 to PTD (PTD-hFOXP3), and explored its function in T cells. The results showed that the PTD rapidly and effectively delivered the hFOXP3 protein into cells where it localized not only in the cytoplasm, but also to the nucleus. PTD-hFOXP3-transduced Jurkat cells (human T lymphoma cell line) and CD4+CD25 T cells failed to proliferate and produce IL-2 and IFN-γ, but produced large amounts of the cytokines IL-4, IL-10, and TGF-β, in response to TCR stimulation in vitro. PTD-hFOXP3-transduced CD4+CD25 T cells also expressed high levels of CTLA-4 and low levels of CD25 after stimulation. Most importantly, PTD-hFOXP3-transduced T cells inhibited the proliferation of activated CD4+CD25 T cells. Furthermore, chromatin immunoprecipitation assays demonstrated that PTD-hFOXP3 can bind with the IL-2 gene promoter and repress the expression of IL-2. These results indicate that PTD-hFOXP3 has the capability to convert conventional T cells to Treg-like cells. J. Cell. Biochem. 113: 3797–3809, 2012. © 2012 Wiley Periodicals, Inc.

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