Elsevier

Stem Cell Research

Volume 7, Issue 1, July 2011, Pages 66-74
Stem Cell Research

Regular article
Mesenchymal stromal cells up-regulate CD39 and increase adenosine production to suppress activated T-lymphocytes

https://doi.org/10.1016/j.scr.2011.04.001Get rights and content
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Abstract

Mesenchymal stromal cells (MSCs) suppress T cell responses through mechanisms not completely understood. Adenosine is a strong immunosuppressant that acts mainly through its receptor A2a (ADORA2A). Extracellular adenosine levels are a net result of its production (mediated by CD39 and CD73), and of its conversion into inosine by Adenosine Deaminase (ADA). Here we investigated the involvement of ADO in the immunomodulation promoted by MSCs. Human T lymphocytes were activated and cultured with or without MSCs. Compared to lymphocytes cultured without MSCs, co-cultured lymphocytes were suppressed and expressed higher levels of ADORA2A and lower levels of ADA. In co-cultures, the percentage of MSCs expressing CD39, and of T lymphocytes expressing CD73, increased significantly and adenosine levels were higher. Incubation of MSCs with media conditioned by activated T lymphocytes induced the production of adenosine to levels similar to those observed in co-cultures, indicating that adenosine production was mainly derived from MSCs. Finally, blocking ADORA2A signaling raised lymphocyte proliferation significantly. Our results suggest that some of the immunomodulatory properties of MSCs may, in part, be mediated through the modulation of components related to adenosine signaling. These findings may open new avenues for the development of new treatments for GVHD and other inflammatory diseases.

Research Highlights

► Mesenchymal Stromal Cells produce adenosine to suppress T-lymhocytes. ► Regulatory T-cells generated by Mesenchymal Stromal Cells express high levels of CD73. ► CD39 is up-regulated by Mesenchymal Stromal Cells to suppress T-lymphocytes. ► Adenosine receptor antagonist partially restores T-cell proliferation.

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