Modulatory activity of adenosine on the immune response in cord and adult blood

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Impact

  • 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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Fig. 1: CD39 expression on freshly isolated cord blood and peripheral blood immune effector cells.
Fig. 2: CD73 expression on cord blood and peripheral blood immune effector cells.
Fig. 3: CD33+ MDSC induction in PBMCs and CBMCs in the presence of adenosine and granulocyte–macrophage colony-stimulating factor (GM-CSF) after 7 days.
Fig. 4: T cell proliferation inhibition by induced MDSCs.
Fig. 5: Expression of IDO (indoleamine-2,3-dioxygenase) and ArgI (arginase I) in the presence and absence of adenosine.
Fig. 6: Expression of adenosine receptors A2A and A3 on immune effector cells.

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Acknowledgements

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.

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F.Ď., N.K.-G. and C.G.: substantial contributions to conception and design; F.Ď.: acquisition of data, or analysis and interpretation of data; F.Ď., C.G.: drafting the article or revising it critically for important intellectual content; C.G., C.F.P.: revising the manuscript and final approval of the version to be published.

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Correspondence to Christian Gille.

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All parents gave written informed consent. The study protocol was approved by ethics committee of the Medical Faculty of Tuebingen University, application number 248/2005A.

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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

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