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

Clin Exp Immunol. 2013 Nov;174(2):302-17. doi: 10.1111/cei.12177.

Abstract

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.

Keywords: B cells; antigen-presenting cells; autoimmunity; immunomodulation; immunosuppressive.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1 / metabolism
  • Antigens, CD19 / metabolism
  • B-Lymphocytes, Regulatory / immunology*
  • CD24 Antigen / metabolism
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Diabetes Mellitus, Type 1 / immunology*
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Immune Tolerance
  • Immunosuppression
  • T-Lymphocytes, Regulatory / immunology
  • Tretinoin / immunology
  • Tretinoin / metabolism

Substances

  • Antigens, CD19
  • CD24 Antigen
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Tretinoin
  • ADP-ribosyl Cyclase 1