Retinoic acid-producing, ex-vivo-generated human tolerogenic dendritic cells induce the proliferation of immunosuppressive B lymphocytes

Authors

  • V. Di Caro,

    1. Department of Pediatrics, Division of Immunogenetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    2. RiMed Foundation, Palermo, Italy
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  • B. Phillips,

    1. Penn State University Hershey Medical Center, Hershey, PA, USA
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  • C. Engman,

    1. Department of Pediatrics, Division of Immunogenetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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  • J. Harnaha,

    1. Department of Pediatrics, Division of Immunogenetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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  • M. Trucco,

    1. Department of Pediatrics, Division of Immunogenetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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  • N. Giannoukakis

    Corresponding author
    1. Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    • Department of Pediatrics, Division of Immunogenetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Correspondence: Nick Giannoukakis, Department of Pathology, University of Pittsburgh School of Medicine, Diabetes Institute, Rangos Research Center 6123, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.

E-mail: ngiann1@pitt.edu

Summary

While much is known about tolerogenic dendritic cell effects on forkhead box protein 3 (FoxP3)+ regulatory T cells, virtually nothing is known about their effects on another arm of immunoregulation that is mediated by a subpopulation of immunosuppressive B cells. These cells suppress rheumatoid arthritis, lupus and inflammatory bowel disease in mice, and functional defects have been reported in human lupus. We show that co-stimulation-impaired tolerogenic dendritic cells that prevent and reverse type 1 diabetes mellitus induce the proliferation of human immunosuppressive B cells in vitro. We also show that the suppressive properties of these B cells concentrate inside the CD19+CD24+ B cell population and more specifically inside the CD19+CD24+CD38+ regulatory B cell population. We discovered that B cell conversion into suppressive cells in vitro is partially dependent on dendritic cell production of retinoic acid and also that CD19+CD24+CD38+ B regulatory cells express retinoic acid receptors. Taken together, our data suggest a model whereby part of the immunosuppressive properties of human tolerogenic dendritic cells could be mediated by retinoic acid which, in addition to its known role in favouring T cell differentiation to FoxP3+ regulatory T cells, acts to convert B cells into immunosuppressive cells.

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