Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FOXP3

Authors

  • Sarah E. Allan,

    1. Department of Surgery, University of British Columbia, Vancouver, Canada
    2. Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada
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  • George X. Song-Zhao,

    1. Department of Surgery, University of British Columbia, Vancouver, Canada
    2. Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada
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  • Thomas Abraham,

    1. James Hogg iCAPTURE Centre, St. Paul's Hospital, University of British Columbia, Vancouver, Canada
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  • Alicia N. McMurchy,

    1. Department of Surgery, University of British Columbia, Vancouver, Canada
    2. Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada
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  • Megan K. Levings

    Corresponding author
    1. Department of Surgery, University of British Columbia, Vancouver, Canada
    2. Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada
    • Department of Surgery, University of British Columbia, 2660 Oak St. Vancouver, BC, Canada V6H 3Z6 Fax: +1−604−875−4497
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Abstract

FOXP3 is required for the development of Treg and its expression is often used as a surrogate marker of functional suppression. However, it is now known that activated human T effector cells can also express FOXP3 without acquiring regulatory activity. To more closely examine the requirements for FOXP3 to reprogram human T cells into Treg, we developed a conditionally active form of FOXP3 and show here that full acquisition of Treg phenotype and function is strictly dependent on the amount of active FOXP3 a T cell expresses. In addition, the phenotypic and functional alterations induced by FOXP3 are only fully manifested following prolonged induction of protein activity. Induction of FOXP3 activity does not upregulate EBI3 or p35 mRNA, providing evidence that secretion of IL-35 does not substantially contribute to the suppressive mechanism of human Treg. These data represent the first formal evidence that FOXP3 acts as a quantitative regulator rather than a simple molecular switch for Treg.

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