CD39-mediated effect of human bone marrow-derived mesenchymal stem cells on the human Th17 cell function

Abstract

This study investigated the immune-modulatory effects of human bone marrow-derived mesenchymal stem cells (hBMSCs) on human Th17 cell function through the CD39-mediated adenosine-producing pathway. The suppressive effects of hBMSCs were evaluated by assessing their effects on the proliferation of Th17 cells and the secretion of interferon (IFN)-γ and interleukin (IL)-17A by Th17 cells with or without anti-CD39 treatment. Changes in CD39 and CD73 expression on the T cells with or without co-culture of hBMSCs were evaluated by flow cytometry. hBMSCs effectively suppressed the proliferation of Th17 cells and the secretion of both IL-17A and IFN-γ from Th17 cells using by both flow cytometry and ELISA, while anti-CD39 treatment significantly reduced the inhibitory effects of hBMSCs on the proliferation and secretion of the Th17 cells. The hBMSCs induced increased expression of the CD39 and CD73 on T cells correlated with the suppressive function of hBMSCs, which was accompanied by increased adenosine production. Our data suggests that hBMSCs can effectively suppress immune responses of the Th17 cells via the CD39-CD73-mediated adenosine-producing pathway.

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

“…Adding a parenthesis to this subject, CD39 expression by MSCs has been subject to conflicting observations [177]. In contrast to our observations [175] and others [178,179], some authors describe a lack or low CD39 expression by MSCs [176,180]. In our view, this might be due to specific experiment design or to antibody variation.…”

“…Since NK-cells already express CD39, which is kept in stable levels in the presence of MSCs, CD73 completes the adenosine framework, and in fact, NK-cells themselves end up producing adenosine and inactivating themselves [181]. Such event was also observed in Th-17 cells, which increased their CD39 and CD73 upon coculture with MSCs and had their activation suppressed by adenosinerelated mechanisms [179].…”

The MSC curtain that stops the immune system

“…However, the frequency of adenosine receptor expression has yet to be determined for MSCs. CD39 may be expressed on a small subset of MSCs, but its activity can also be contributed by its presence on other cells that lie adjacent to MSCs [43][44][45]. Thus, this trio of cell surface molecules exert localized functions that include: anti-inflammatory activities, immuno-supressive activities, and pro-angiogenic activities.…”

“…Thus, new studies are needed to assess the role of hypoxia in regulating the function of this molecule on MSC function. In vitro studies have shown that mixing human or mouse MSCs with Th1 or Th17 cells results in the upregulation of adenosine production by MSCs [43,[45][46][47]. Further, adenosine produced in this manner suppresses the functional activity of these T-cells and may induce apoptosis in these populations.…”

Stem Cell Considerations for the Clinician

“…Co-cultures of MSC suppress proliferation of stimulated mononuclear cells (33) or T-lymphocytes (34) (35) and Fas ligand-mediated apoptosis of T-cells (36). The interaction of T1 or T17 lymphocytes upregulates adenosine production by MSC that suppresses these lymphocyte populations (37) (38) and leads to new blood vessel formation through stimulation of vascular endothelial growth factor (39). The interaction of MSC and monocytes results in their production of IL-10 and an anti-inflammatory phenotype (40).…”