Immunoregulatory role of nucleated erythroid cells

• Roman Yu. Zavodskii
• Yulia A. Shevchenko
• Olga Yu. Koneva
• Kirill V. Nazarov
• Maria S. Kuznetsova
• Sergey V. Sennikov

Abstract

Nucleated erythroid cells (NEC) are the precursors of the most massive population of human cells – erythrocytes, for which functions of hemo- and immunoregulation have been shown at various stages of ontogenesis and in various organs and tissues of the human body. NEC perform this function by secreting cytokine proteins, growth factors, enzymes such as arginase-2, ROS, and by surface molecules PD-L1 and PD-L2. Their important regulatory role has been shown for the formation of fetoplacental immunosuppression, immunosuppression during pregnancy, suppression of the response against commensals in the gastrointestinal tract, in the pathogenesis of bacterial and viral infections in adults, in the pathogenesis of tumor growth and autoimmune diseases, as well as participation in the recognition of pathogen-associated molecular patterns using Toll-like receptors in fish and birds. Such qualities, together with their number and width of distribution, represent NEC as active participants in hemo- and immunoregulation, which makes it important to study their regulatory role in health and disease.

Keywords:nucleated erythroid cells; erythroblasts; cytokines; immunosuppression; innate immunity; fetomaternal immunosuppression; inflammatory bowel disease; tumor immunosuppression; COVID-2019; SARS-CoV-2

References

1. Sender R., Fuchs S., Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016; 14 (8): e1002533. DOI: https://doi.org/10.1371/journal.pbio.1002533

2. Amon S., Meier-Abt F., Gillet L.C., Dimitrieva S., et al. Sensitive quantitative proteomics of human hematopoietic stem and progenitor cells by data-independent acquisition mass spectrometry. Mol. Cell. Proteomics. 2019; 18 (7): 1454–67. DOI: https://doi.org/10.1074/mcp.TIR119. 001431

3. Marsee D.K., Pinkus G.S., Yu H. CD71 (transferrin receptor) an effective marker for erythroid precursors in bone marrow biopsy specimens. Am. J. Clin. Pathol. 2010; 134 (3): 429–35. DOI: https://doi.org/10.1309/AJCPCRK3MOAOJ6AT

4. Van Lochem E.G., Van der Velden V.H., Wind H.K., Te Marvelde J.G., et al. Immunophenotypic differentiation patterns of normal hematopoiesis in human bone marrow: reference patterns for age-related changes and disease-induced shifts. Cytometry B Clin. Cytom. 2004; 60 (1): 1–13. DOI: https://doi.org/10.1002/cyto.b.20008

5. Elahi S., Mashhouri S. Immunological consequences of extramedullary erythropoiesis: immunoregulatory functions of CD71⁺ erythroid cells. Haematologica. 2020; 105 (6): 1478–83. DOI: https://doi.org/10.3324/haematol.2019.243063

6. Delyea C., Bozorgmehr N., Koleva P., Dunsmore G., et al. CD71⁺ erythroid suppressor cells promote fetomaternal tolerance through arginase-2 and PD-L1. J. Immunol. 2018; 200 (12): 4044–58. DOI: https://doi.org/10.4049/jimmunol.1800113

7. de Macario E.C., Macario A.J. A new kind of immunosuppression associated with erythropoiesis. Immunol. Lett. 1979; 1 (1): 23–6. DOI: https://doi.org/10.1016/0165-2478(79)90032-4

8. Kozlov V.A., Tsyrlova I.G., Cheglyakova V.V. Immunoregulatory cells of non-lymphocytic nature – ER-suppressors. Doklady AN SSSR. 1984; 275 (1): 247–9. (in Russian)

9. Mitasov A.V., Chernykh E.R., Tsyrlova I.G., Shubinsky G.Z., Kozlov V.A. Effects of ER-suppressor factor(s) on the proliferation of human lymphocytes. Immunologiya. 1990; 11 (5): 61–3. (in Russian)

10. Sennikov S.V., Kashlakova N.V., Sanin A.V., Tsyrlova I.G., Kozlov V.A. Study of the role of T-lymphocytes in immunosuppression by erythroid cells. Immunologiya. 1987; 8 (3): 36–8. (in Russian)

11. Seledtsov V.I., Seledtsova G.V., Samarin D.M., Taraban V.Y., et al. Characterization of erythroid cell-derived natural suppressor activity. Immunobiology. 1998; 198 (4): 361–74. DOI: https://doi.org/10.1016/S0171-2985(98)80045-4

12. Seledtsova G.V., Seledtsov V.I., Samarin D.M., Senyukov V.V., et al. Erythroid cells in immunoregulation: characterization of a novel suppressor factor. Immunol. Lett. 2004; 93 (2–3): 171–8. DOI: https://doi.org/10.1016/j.imlet.2004.03.011

13. Sennikov S.V, Eremina L.V., Injelevskaya T.V., Krysov S.V., et al. Cytokine-synthesizing activity of erythroid cells. Russ. J. Immunol. 2001; 6 (2): 193–202.

14. Sennikov S.V., Eremina L.V., Samarin D.M., Avdeev I.V., et al. Cytokine gene expression in erythroid cells. Eur. Cytokine Netw. 1996; 7 (4): 771–4.

15. Sennikov S.V., Injelevskaya T.V., Krysov S.V., Silkov A.N., et al. Production of hemo- and immunoregulatory cytokines by erythroblast antigen+ and glycophorin A+ cells from human bone marrow. BMC Cell Biol. 2004; 5 (1): 1–6. DOI: https://doi.org/10.1186/1471-2121-5-39

16. Sennikov S.V., Inzhelevskaya T.V., Eremina L.V., Kozlov V.A. Regulation of functional activity of bone marrow hemopoietic stem cells by erythroid cells in mice. Bull. Exp. Biol. Med. 2000; 130 (6): 1159–61.

17. Sennikov S.V., Krysov S.V., Injelevskaya T.V., Silkov A.N., et al. Production of cytokines by immature erythroid cells derived from human embryonic liver. Eur. Cytokine Netw. 2001; 12 (2): 274–9.

18. Silkov A.N., Inzhelevskaya T.V., Krysov S.V., Sennikov S.V., Kozlov V.A. Expression of mRNA splice variants of IL-4 and IL-6 genes in human erythroid cells. Sibirskiy nauchniy meditsinskiy zhurnal. 2007; 4: 129–31. (in Russian)

19. Denisova V.V., Kulagin A.D., Lisukov I.A., Kryuchkova I.V., et al. Cytokine-producing activity of bone marrow erythrokaryocytes and its regulation under normal conditions. Bull. Exp. Biol. Med. 2007; 143 (2): 218–21. DOI: https://doi.org/10.1007/s10517-007-0055-5

20. Kashlakova N.V., Lisukov I.A., Tsyrlova I.G., Vasil’ev N.V., Kozlov V.A. Suppressive effect of blast cells in AKR mice on antibody production in vivo and lymphocyte proliferation in vitro. Byulleten’ eksperimental’noi biologii i meditsiny. 1988; 105 (2): 184–6. (in Russian)

21. Chen X., Song M., Zhang B., Zhang Y. Reactive oxygen species regulate T cell immune response in the tumor microenvironment. Oxid. Med. Cell. Longev. 2016; 2016: 1580967. DOI: https://doi.org/10.1155/2016/1580967

22. Gomez-Lopez N., Romero R., Xu Y., Miller D., et al. Umbilical cord CD 71⁺ erythroid cells are reduced in neonates born to women in spontaneous preterm labor. Am. J. Reprod. Immunol. 2016; 76 (4): 280–4. DOI: https://doi.org/10.1111/aji.12556

23. Rincon M.R., Oppenheimer K., Bonney E.A. Selective accumulation of Th2-skewing immature erythroid cells in developing neonatal mouse spleen. Int. J. Biol. Sci. 2012; 8 (5): 719–30. DOI: https://doi.org/10.7150/ijbs.3764

24. Dunsmore G., Koleva P., Sutton R.T., Ambrosio L., et al. Mode of delivery by an ulcerative colitis mother in a case of twins: immunological differences in cord blood and placenta. World J. Gastroenterol. 2018; 24 (42): 4787–97. DOI: https://doi.org/10.3748/wjg.v24.i42.4787

25. Elahi S., Ertelt J.M., Kinder J.M., Jiang T.T., et al. Immunosuppressive CD71⁺ erythroid cells compromise neonatal host defence against infection. Nature. 2013; 504 (7478): 158–62. DOI: https://doi.org/10.1038/nature12675

26. Namdar A., Koleva P., Shahbaz S., Strom S., et al. CD71⁺ erythroid suppressor cells impair adaptive immunity against Bordetella pertussis. Sci. Rep. 2017; 7 (1): 1–2. DOI: https://doi.org/10.1038/s41598-017-07938-7

27. Dunsmore G., Koleva P., Ghobakhloo N., Sutton R., et al. Lower abundance and impaired function of CD71⁺ erythroid cells in inflammatory bowel disease patients during pregnancy. J. Crohns Colitis. 2019; 13 (2): 230–44. DOI: https://doi.org/10.1093/ecco-jcc/jjy147

28. Zhao L., He R., Long H., Guo B., et al. Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat. Med. 2018; 24 (10): 1536–44. DOI: https://doi.org/10.1038/s41591-018-0205-5

29. Kang J., Perry J.K., Pandey V., Fielder G.C., et al. Artemin is oncogenic for human mammary carcinoma cells. Oncogene. 2009; 28 (19): 2034–45. DOI: https://doi.org/10.1038/onc.2009.66

30. Han Y., Liu Q., Hou J., Gu Y., et al. Tumor-induced generation of splenic erythroblast-like Ter-cells promotes tumor progression. Cell. 2018; 173 (3): 634–48. DOI: https://doi.org/10.1016/j.cell.2018. 02.061

31. Rodriguez M.F., Wiens G.D., Purcell M.K., Palti Y. Characterization of Toll-like receptor 3 gene in rainbow trout (Oncorhynchus mykiss). Immunogenetics. 2005; 57 (7): 510–9. DOI: https://doi.org/10.1007/s00251-005-0013-1

32. Morera D., Roher N., Ribas L., Balasch J.C., et al. RNA-Seq reveals an integrated immune response in nucleated erythrocytes. PLoS One. 2011; 6 (10): e26998. DOI: https://doi.org/10.1371/journal.pone.0026998

33. St Paul M., Paolucci S., Barjesteh N., Wood R.D., et al. Chicken erythrocytes respond to Toll-like receptor ligands by up-regulating cytokine transcripts. Res. Vet. Sci. 2013; 95 (1): 87–91. DOI: https://doi.org/10.1016/j.rvsc.2013.01.024

34. Chen N., Zhou M., Dong X., Qu J., et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395 (10 223): 507–13. DOI: https://doi.org/10.1016/S0140-6736(20)30211-7

35. Shahbaz S., Xu L., Osman M., Sligl W., et al. Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2. Stem Cell Rep. 2021; 16 (5): 1165–81. DOI: https://doi.org/10.1016/j.stemcr.2021.04.001

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)