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



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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    Elahi, S. et al. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 504, 158–162 (2013).

    CAS  Article  Google Scholar 

  2. 2.

    Levy, O. et al. The adenosine system selectively inhibits TLR-mediated TNF-α production in the human newborn. J. Immunol. 177, 1956–1966 (2006).

    CAS  Article  Google Scholar 

  3. 3.

    Bono, M. R. et al. CD73 and CD39 ectonucleotidases in T cell differentiation: beyond immunosuppression. FEBS Lett. 589, 3454–3460 (2015).

    CAS  Article  Google Scholar 

  4. 4.

    Martin, C. et al. High adenosine plasma concentration as a prognostic index for outcome in patients with septic shock. Crit. Care Med. 28, 3198–3202 (2000).

    CAS  Article  Google Scholar 

  5. 5.

    Sottofattori, E., Anzaldi, M. & Ottonello, L. HPLC determination of adenosine in human synovial fluid. J. Pharm. Biomed. Anal. 24, 1143–1146 (2001).

    CAS  Article  Google Scholar 

  6. 6.

    Chen, Y. et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314, 1792–1795 (2006).

    CAS  Article  Google Scholar 

  7. 7.

    Schenk, U. et al. Purinergic control of T cell activation by ATP released through pannexin-1 hemichannels. Sci. Signal. 1, ra6–ra6 (2008).

    Article  Google Scholar 

  8. 8.

    Eltzschig, H. K., Weissmüller, T., Mager, A. & Eckle, T. Nucleotide metabolism and cell-cell interactions. Methods Mol Biol. 341, 73–87. (2006).

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Eltzschig, H. K. et al. Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. Blood 104, 3986–3992 (2004).

    CAS  Article  Google Scholar 

  10. 10.

    Colgan, S. P. et al. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium. J. Exp. Med. 198, 783–796 (2003).

    Article  Google Scholar 

  11. 11.

    Synnestvedt, K. et al. Ecto-5’-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J. Clin. Investig. 110, 993–1002 (2002).

    CAS  Article  Google Scholar 

  12. 12.

    Thompson, L. F. et al. Crucial role for ecto-5’-nucleotidase (CD73) in vascular leakage during hypoxia. J. Exp. Med. 200, 1395–1405 (2004).

    CAS  Article  Google Scholar 

  13. 13.

    Ehrentraut, H. et al. CD73+ regulatory T cells contribute to adenosine-mediated resolution of acute lung injury. FASEB J. 27, 2207–2219 (2013).

    CAS  Article  Google Scholar 

  14. 14.

    Grenz, A., Homann, D. & Eltzschig, H. K. Extracellular adenosine: a safety signal that dampens hypoxia-induced inflammation during ischemia. Antioxid. Redox Signal. 15, 2221–2234 (2011).

    CAS  Article  Google Scholar 

  15. 15.

    Koeppen, M., Eckle, T. & Eltzschig, H. K. Selective deletion of the A1 adenosine receptor abolishes heart-rate slowing effects of intravascular adenosine in vivo. PLoS ONE 4, e6784 (2009).

    Article  Google Scholar 

  16. 16.

    Rieber, N. et al. Neutrophilic myeloid-derived suppressor cells in cord blood modulate innate and adaptive immune responses. Clin. Exp. Immunol. 174, 45–52 (2013).

    CAS  Article  Google Scholar 

  17. 17.

    Köstlin, N. et al. Granulocytic myeloid derived suppressor cells expand in human pregnancy and modulate T-cell responses. Eur. J. Immunol. 44, 2582–2591 (2014).

    Article  Google Scholar 

  18. 18.

    Köstlin, N. et al. Granulocytic myeloid-derived suppressor cells accumulate in human placenta and polarize toward a Th2 phenotype. J. Immunol. 196, 1132–1145 (2016).

    Article  Google Scholar 

  19. 19.

    Dowling, D. J. & Levy, O. Ontogeny of early life immunity. Trends Immunol. 35, 299–310 (2014).

    CAS  Article  Google Scholar 

  20. 20.

    Pagel, J. et al. Regulatory T cell frequencies are increased in preterm infants with clinical early-onset sepsis. Clin. Exp. Immunol. 185, 219–227 (2016).

    CAS  Article  Google Scholar 

  21. 21.

    Boyum, A. Separation of leukocytes from blood and bone marrow. Introduction. Scand. J. Clin. Lab. Invest. Suppl. 97, 7 (1968).

    CAS  PubMed  Google Scholar 

  22. 22.

    Boyum, A. Separation of lymphocytes, lymphocyte subgroups and monocytes: a review. Lymphology 10, 71–76 (1977).

    CAS  PubMed  Google Scholar 

  23. 23.

    Lechner, M. G., Liebertz, D. J. & Epstein, A. L. Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J. Immunol. 185, 2273–2284 (2010).

    CAS  Article  Google Scholar 

  24. 24.

    Köstlin, N. et al. HLA-G promotes myeloid-derived suppressor cell accumulation and suppressive activity during human pregnancy through engagement of the receptor ILT4. Eur. J. Immunol. 47, 374–384 (2017).

    Article  Google Scholar 

  25. 25.

    Degheidy, H. A. et al. Methodological comparison of two anti-ZAP-70 antibodies. Cytom. Part B 80B, 300–308 (2011).

    CAS  Article  Google Scholar 

  26. 26.

    Allard, B. et al. The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets. Immunol. Rev. 276, 121–144 (2017).

    CAS  Article  Google Scholar 

  27. 27.

    Reutershan, J. et al. Adenosine and inflammation: CD39 and CD73 are critical mediators in LPS‐induced PMN trafficking into the lungs. FASEB J. 23, 473–482 (2008).

    Article  Google Scholar 

  28. 28.

    Laver, J. et al. High levels of granulocyte and granulocyte-macrophage colony-stimulating factors in cord blood of normal full-term neonates. J. Pediatr. 116, 627–632 (1990).

    CAS  Article  Google Scholar 

  29. 29.

    Fiehn, C. et al. Plasma GM-CSF concentrations in rheumatoid arthritis, systemic lupus erythematosus and spondyloarthropathy. Z. Rheumatol. 51, 121–126 (1992).

    CAS  PubMed  Google Scholar 

  30. 30.

    Omori, F. et al. Levels of human serum granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor under pathological conditions. Biotherapy 4, 147–153 (1992).

    CAS  Article  Google Scholar 

  31. 31.

    Ryzhov, S. et al. Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+Gr1+cells. J. Immunol. 187, 6120–6129 (2011).

    CAS  Article  Google Scholar 

  32. 32.

    Nowak, M. et al. The A2aR adenosine receptor controls cytokine production in iNKT cells. Eur. J. Immunol. 40, 682–687 (2010).

    CAS  Article  Google Scholar 

  33. 33.

    Regateiro, F. S. et al. Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-beta. Eur. J. Immunol. 41, 2955–2965 (2011).

    CAS  Article  Google Scholar 

  34. 34.

    Kropf, P. et al. Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy. Eur. J. Immunol. 37, 935–945 (2007).

    CAS  Article  Google Scholar 

  35. 35.

    Rivkees, S. A. et al. Influences of adenosine on the fetus and newborn. Mol. Genet. Metab. 74, 160–171 (2001).

    CAS  Article  Google Scholar 

  36. 36.

    Ehrentraut, H. et al. Adora2b adenosine receptor engagement enhances regulatory T cell abundance during endotoxin-induced pulmonary inflammation. PLoS ONE 7, e32416 (2012).

    CAS  Article  Google Scholar 

  37. 37.

    Eltzschig, H. K., Bonney, S. K. & Eckle, T. Attenuating myocardial ischemia by targeting A2B adenosine receptors. Trends Mol. Med. 19, 345–354 (2013).

    CAS  Article  Google Scholar 

  38. 38.

    Leone, R. D. & Emens, L. A. Targeting adenosine for cancer immunotherapy. J. Immunother. Cancer 6, 57 (2018).

    Article  Google Scholar 

  39. 39.

    Iris, M., Tsou, P.-S. & Sawalha, A. H. Caffeine inhibits STAT1 signaling and downregulates inflammatory pathways involved in autoimmunity. Clin. Immunol. 192, 68–77 (2018).

    CAS  Article  Google Scholar 

  40. 40.

    Speer, E. M. et al. Pentoxifylline, dexamethasone and azithromycin demonstrate distinct age-dependent and synergistic inhibition of TLR- and inflammasome-mediated cytokine production in human newborn and adult blood in vitro. PLoS ONE 13, e0196352 (2018).

    Article  Google Scholar 

Download references


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.

Author information




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.

Corresponding author

Correspondence to Christian Gille.

Ethics declarations

Competing interests

The authors declare no competing interests.

Statement of consent

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation


Quick links