Neonatal sepsis is a leading cause of neonatal morbidity and mortality, associated with immunosuppression. Myeloid-derived suppressor cells (MDSCs) are cells with immunosuppressive activity, present in high amounts in cord blood. Mechanisms regulating MDSC expansion are incompletely understood. Adenosine is a metabolite with immunoregulatory effects that are elevated in cord blood.
Impact of adenosine on peripheral and cord blood mononuclear cells (PBMCs and CBMCs) was analysed by quantification of ectonucleotidases and adenosine receptor expression, MDSC induction from PBMCs and CBMCs, their suppressive capacity on T cell proliferation and effector enzyme expression by flow cytometry.
Cord blood monocytes mainly expressed CD39, while cord blood T cells expressed CD73. Adenosine-induced MDSCs from PBMCs induced indoleamine-2,3-dioxygenase (IDO) expression and enhanced arginase I expression in monocytes. Concerted action of IDO and ArgI led to effective inhibition of T cell proliferation. In addition, adenosine upregulated inhibitory A3 receptors on monocytes.
Adenosine acts by inducing MDSCs and upregulating inhibitory A3 receptors, probably as a mode of autoregulation. Thus, adenosine contributes to immunosuppressive status and may be a target for immunomodulation during pre- and postnatal development.
Immune effector cells, that is, monocytes, T cells and MDSCs from cord blood express ectonucleotidases CD39 and CD73 and may thus serve as a source for adenosine as an immunomodulatory metabolite.
Adenosine mediates its immunomodulatory properties in cord blood by inducing MDSCs, and by modulating the inhibitory adenosine A3 receptor on monocytes.
Adenosine upregulates expression of IDO in MDSCs and monocytes potentially contributing to their suppressive activity.
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This project was funded by The Federal Ministry of Education and Research (BMBF) grant no GFGL1165817-01 GL1746F to C.G. and The Ministry of Science, Research and Art Baden-Württemberg and The European Social Fund to N.K.-G.
The authors declare no competing interests.
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Ďurčo, F., Köstlin-Gille, N., Poets, C.F. et al. Modulatory activity of adenosine on the immune response in cord and adult blood. Pediatr Res (2021). https://doi.org/10.1038/s41390-020-01275-8