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

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.