A Novel Mechanism of B Cell–Mediated Immune Suppression through CD73 Expression and Adenosine Production

Abstract

Immune suppression by regulatory T (Treg) cells and regulatory B (Breg) cells is a critical mechanism to limit excess inflammation and autoimmunity. IL-10 is considered to be the major mediator of B cell-induced immune suppression. Here, we report a novel mechanism for immune suppression through adenosine generation by B cells. We identified a novel population of B cells that expresses CD73 as well as CD39, two ecto-enzymes that together catalyze the extracellular dephosphorylation of adenine nucleotides to adenosine. Whereas CD39 expression is common among B cells, CD73 expression is not. Approximately 30–50% of B-1 cells (B220+CD23−) and IL-10 producing B (B10) cells (B220+CD5+CD1dhi) are CD73hi, depending on mouse strain, whereas few conventional B-2 cells (B220+CD23+AA4.1−) express CD73. In keeping with expression of both CD73 and CD39, we found that CD73+ B cells produce adenosine in the presence of substrate whereas B-2 cells don’t. CD73−/− mice were more susceptible to dextran sulfate sodium salt (DSS)-induced colitis than wild type (WT) mice, and transfer of CD73+ B cells ameliorated the severity of colitis, suggesting that B cell CD73/CD39/adenosine can modulate DSS-induced colitis. IL-10 production by B cells is not affected by CD73-deficiency. Interestingly, adenosine generation by IL-10−/− B cells is impaired due to reduced expression of CD73, indicating an unexpected connection between IL-10 and adenosine and suggesting caution in interpreting the results of studies with IL-10−/− cells. Together our findings demonstrate a novel regulatory role of B cells on colitis through adenosine generation in an IL-10-independent manner.

The regulatory role of B cells in autoimmunity, infections and cancer: Perspectives beyond IL10 production

“…Finally, there is evidence that B cells would regulate immunity not only through cytokine production but also via surface molecules, such as CD39, CD73 and Programmed death-ligand 1 (PD-L1). Indeed, a novel population of B cells has been shown to regulate colitis in an IL-10-independent manner but dependent on the expression of CD39 and CD73 [29]. CD39 is an ectonucleoside triphosphate diphosphohydrolase-1 and CD73 is an ecto-5 0 -nucleotidase which hydrolyze exogenous adenosine triphosphate (ATP) to adenosine 5 0 -monophosphate (AMP) and finally produce immunosuppressive adenosine (ADO) [30][31][32].…”

“…CD39 is an ectonucleoside triphosphate diphosphohydrolase-1 and CD73 is an ecto-5 0 -nucleotidase which hydrolyze exogenous adenosine triphosphate (ATP) to adenosine 5 0 -monophosphate (AMP) and finally produce immunosuppressive adenosine (ADO) [30][31][32]. In the dextran sulfate sodium salt-induced colitis murine model, transfer of ADOproducing CD73 + B1 cells conferred resistance to the colitis susceptible CD73 À/À mice [29]. In addition, experiments performed by Saze and collaborators [33] demonstrated that upon activation, human B cells increase their expression of CD39 and acquire the capability to downregulate proliferation of autologous CD4 + or CD8 + T cells.…”

Rapid activation and hepatic recruitment of innate-like regulatory B cells after invariant NKT cell stimulation in mice

“…B1 cells in particular express cell surface CD73, an ectoenzyme critically important for generating adenosine [30]. We found that hepatic numbers of both CD73 + B1a and B1b B cells significantly increase post-αGalCer administration ( Fig.…”

“…In a series of experiments we addressed potential mechanisms whereby B cell depletion augments αGalCer-induced liver injury, including altering iNKT cell activation [34] and proinflammatory cytokine production (specifically IL-4 and TNFα) [2,5,6], enhancing hepatic recruitment of neutrophils and/or γδ T cells (both implicated in αGalCer-induced hepatitis) [11,12], and the potential loss of B cell derived anti-inflammatory cytokines (IL-10 and/or TGFβ) [13,[15][16][17] or the capacity to generate anti-inflammatory mediators (ie adenosine) [29,30] within the liver.…”

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

“…In this sense, it should be noted that endothelial cells express CD39 and CD73 on their surface and can be a source of adenosine [102]. Furthermore, it has recently been demonstrated both in mice and in humans that B-cells express CD39 and CD73, produce adenosine and inhibit T-cell proliferation [103,104]. Likewise, CD56 bright CD16…”