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

Abstract

SummaryWhile 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-stimulationimpaired 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.

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

“…Although data regarding the effects on beta cell function and survival remain controversial [45,46], IL-6 may also stimulate beta cell repair. Thus, in DC-MSC combination therapy, multiple layers of tolerance could be formed involving regulatory DCs, T cells and even B cells [47] that may act and accumulate in relevant tissue.…”

The Effect of Vitamin A Supplementation on FoxP3 and TGF-β Gene Expression in Avonex-Treated Multiple Sclerosis Patients

“…Several mediators can induce Treg cell development including TGF-β and retinoic acid (RA) (Hall et al 2011;Caro et al 2013).…”

The Molecular Mechanisms of Vitamin A Deficiency in Multiple Sclerosis

“…Development of iTregs relies on several mediators including IL-12, TGF-β and RA (Hall et al 2011;Di Caro et al 2013). It has been observed that treating cell-cultured splenic DCs with RA and TGF-β significantly induced iTreg development , Di Caro et al 2013.…”

“…Development of iTregs relies on several mediators including IL-12, TGF-β and RA (Hall et al 2011;Di Caro et al 2013). It has been observed that treating cell-cultured splenic DCs with RA and TGF-β significantly induced iTreg development , Di Caro et al 2013. Retinoic acid also promotes the production of IL-10, which is essential for optimal action of Tregs (Wang et al 2007;Boks et al 2012).…”

“…These act as part of the tolerogenic cell network, which includes Tregs and DCs (Benson et al 2007). In vitro studies have shown that RA-producing DCs enhance Breg cells (Di Caro et al 2013). Also, in in vitro models of T cell-activated B cells, RA can reduce B cell proliferation through several mechanisms, including cell cycle arrest via altered expression of several cell cycle regulatory factors and negative regulation of the NF-kB pathway, which play major roles in controlling B cell development and proliferation (Cassani et al 2012;Chen et al 2012).…”