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Dendritic cells expand antigen-specific Foxp3+CD25+CD4+ regulatory T cells including suppressors of alloreactivity

Authors

  • Sayuri Yamazaki,

    Corresponding author
    1. Laboratory of Cellular Physiology and Immunology, Chris Browne Center of Immunology and Immune Disease, The Rockefeller University, New York, NY, USA
      Sayuri Yamazaki
      Laboratory for Cellular Physiology and Immunology
      The Rockefeller University
      1230 York Avenue
      Box 176
      New York, NY 10021
      Tel.: +1 212 327 8875
      Fax: +1 212 327 8106
      E-mail: yamazas@rockefeller.edu
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  • Kayo Inaba,

    1. Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
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  • Kristin V. Tarbell,

    1. Laboratory of Cellular Physiology and Immunology, Chris Browne Center of Immunology and Immune Disease, The Rockefeller University, New York, NY, USA
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  • Ralph M. Steinman

    1. Laboratory of Cellular Physiology and Immunology, Chris Browne Center of Immunology and Immune Disease, The Rockefeller University, New York, NY, USA
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Sayuri Yamazaki
Laboratory for Cellular Physiology and Immunology
The Rockefeller University
1230 York Avenue
Box 176
New York, NY 10021
Tel.: +1 212 327 8875
Fax: +1 212 327 8106
E-mail: yamazas@rockefeller.edu

Abstract

Summary:  Thymic derived naturally occurring CD25+CD4+ T regulatory cells (Tregs) suppress immune responses, including transplantation. Here we discuss the capacity of dendritic cells (DCs) to expand antigen-specific Tregs, particularly polyclonal Tregs directed to alloantigens. Initial studies have shown that mature DCs are specialized antigen-presenting cells (APCs) for expanding antigen-specific CD25+ CD4+ Tregs from TCR transgenic mice. When triggered by specific antigen, these Tregs act back on immature DCs to block the upregulation of CD80 and CD86 costimulatory molecules. More recently, DCs have been used to expand alloantigen-specific CD25+CD4+ Tregs from the polyclonal repertoire in the presence of interleukin-2 (IL-2). Allogeneic DCs are much more effective than allogeneic spleen cells for expanding CD25+CD4+ Tregs. The DC-expanded Tregs continue to express high levels of Foxp3, even without supplemental IL-2, whereas spleen cells poorly sustain Foxp3 expression. When suppressive activity is tested, relatively small numbers of DC-expanded CD25+CD4+ Tregs exert antigen-specific suppression in the mixed leukocyte reaction (MLR), blocking immune responses to the original stimulating strain 10 times more effectively than to third party stimulating cells. DC-expanded Tregs also retard graft versus host disease (GVHD) across full major histocompatibility complex (MHC) barriers. In vitro and in vivo, the alloantigen-specific CD25+CD4+ Tregs are much more effective suppressors of transplantation reactions than polyclonal populations. We suggest that the expansion of Tregs from a polyclonal repertoire via antigen-presenting DCs will provide a means for antigen-specific control of unwanted immune reactions.

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