Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Continuous activation of polymorphonuclear myeloid-derived suppressor cells during pregnancy is critical for fetal development

Cellular & Molecular Immunology volume 18, pages 1692–1707 (2021)Cite this article

Subjects

Abstract

The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy. Although studies have shown that myeloid-derived suppressor cells (MDSCs) play an important role in maintaining feto-maternal tolerance, little is known about the role of MDSCs in pregnancies with intrauterine growth retardation (IUGR). Here, we reported that the activation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) during pregnancy was closely associated with fetal growth. In humans, class E scavenger receptor 1 (SR-E1), a distinct marker for human PMN-MDSCs, was used to investigate PMN-MDSC function during pregnancy. Continuous activation of SR-E1+ PMN-MDSCs was observed in all stages of pregnancy, accompanied by high cellular levels of ROS and arginase-1 activity, mediated through STAT6 signaling. However, SR-E1+ PMN-MDSCs in pregnancies with IUGR showed significantly lower suppressive activity, lower arginase-1 activity and ROS levels, and decreased STAT6 phosphorylation level, which were accompanied by an increase in inflammatory factors, compared with those in normal pregnancies. Moreover, the population of SR-E1+ PMN-MDSCs was negatively correlated with the adverse outcomes of newborns from pregnancies with IUGR. In mice, decreases in cell population, suppressive activity, target expression levels, and STAT6 phosphorylation levels were also observed in the pregnancies with IUGR compared with the normal pregnancies, which were rescued by the adoptive transfer of PMN-MDSCs from pregnant mice. Interestingly, the growth-promoting factors (GPFs) secreted by placental PMN-MDSCs in both humans and mice play a vital role in fetal development. These findings collectively support that PMN-MDSCs have another new role in pregnancy, which can improve adverse neonatal outcomes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Erlebacher, A. Immunology of the maternal-fetal interface. Annu. Rev. Immunol. 31, 387–411 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. PrabhuDas, M. et al. Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat. Immunol. 16, 328–334 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Romero, R., Dey, S. K. & Fisher, S. J. Preterm labor: one syndrome, many causes. Science 345, 760–765 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Arck, P. C. & Hecher, K. Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat. Med. 19, 548–556 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Erlebacher, A. et al. Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus. J. Clin. Investig. 117, 1399–1411 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Verdijk, R. M. et al. Pregnancy induces minor histocompatibility antigen-specific cytotoxic T cells: implications for stem cell transplantation and immunotherapy. Blood 103, 1961–1964 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Fu, B. Q. et al. Natural killer cells promote fetal development through the secretion of growth-promoting factors. Immunity 47, 1100–1113 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Msallam, R. et al. Fetal mast cells mediate postnatal allergic responses dependent on maternal IgE. Science 370, 941–950 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. Wang, W., Sung, N. Y., Gilman-Sachs, A. & Kwak-Kim, J. T helper (Th) cell profiles in pregnancy and recurrent pregnancy losses: Th1/Th2/Th9/Th17/Th22/Tfh cells. Front. Immunol. 11, 2025 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Huhn, O. et al. Distinctive phenotypes and functions of innate lymphoid cells in human placenta during early pregnancy. Nat. Commun. 11, 381 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang, L. L. et al. The dynamic profile and potential function of B-cell subsets during pregnancy. Cell. Mol. Immunol. 18, 1082–1084 (2020).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Cai, D. L., Tang, Y. H. & Yao, X. Y. Changes of γδT cell subtypes during pregnancy and their influences in spontaneous abortion. J. Reprod. Immunol. 131, 57–62 (2019).

    Article  PubMed  Google Scholar 

  13. Noman, M. Z. et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211, 781–790 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chabtini, L. et al. TIM-3 regulates innate immune cells to induce fetomaternal tolerance. J. Immunol. 190, 88–96 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. D’Addio, F. et al. The link between the PDL1 costimulatory pathway and Th17 in fetomaternal tolerance. J. Immunol. 187, 4530–4541 (2011).

    Article  PubMed  CAS  Google Scholar 

  16. Hosseini, A. et al. Regulatory T and T helper 17 cells: their roles in preeclampsia. J. Cell. Physiol. 233, 6561–6573 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Gomez-Lopez, N. et al. Regulatory T cells play a role in a subset of idiopathic preterm labor/birth and adverse neonatal outcomes. Cell. Rep. 32, 107874 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mandruzzato, G. et al. Intrauterine restriction (IUGR). J. Perinat. Med. 36, 277–281 (2008).

    Article  PubMed  Google Scholar 

  19. Pilliod, R. A. et al. The risk of intrauterine fetal death in the small-for-gestational-age fetus. Am. J. Obstet. Gynecol. 207, e1–e6.318 (2012).

    Article  Google Scholar 

  20. Sharma, D., Shastri, S., Farahbakhsh, N. & Sharma, P. Intrauterine growth restriction—part 1. J. Matern. Fetal Neonatal Med. 29, 3977–3987 (2016).

    Article  PubMed  Google Scholar 

  21. Veerbeek, J. H. et al. Placental pathology in early intrauterine growth restriction associated with maternal hypertension. Placenta 35, 696–701 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. John, R. M. Imprinted genes and the regulation of placental endocrine function: pregnancy and beyond. Placenta 56, 86–90 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Bronte, V. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gabrilovich, D. I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5, 3–8 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Youn, J. I., Collazo, M., Shalova, I. N., Biswas, S. K. & Gabrilovich, D. I. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J. Leukoc. Biol. 91, 167–181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. He, Y. M. et al. Transitory presence of myeloid-derived suppressor cells in neonates is critical for control of inflammation. Nat. Med. 24, 224–231 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pan, T. et al. 17β-Oestradiol enhances the expansion and activation of myeloid-derived suppressor cells via signal transducer and activator of transcription (STAT)-3 signalling in human pregnancy. Clin. Exp. Immunol. 185, 86–97 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nair, R. R., Sinha, P., Khanna, A. & Singh, K. Reduced myeloid-derived suppressor cells in the blood and endometrium is associated with early miscarriage. Am. J. Reprod. Immunol. 73, 479–486 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Pan, T. et al. Myeloid-derived suppressor cells are essential for maintaining feto-maternal immunotolerance via STAT3 signaling in mice. J. Leukoc. Biol. 100, 499–511 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Condamine, T. et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci. Immunol. 1, aaf8943 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  32. PrabhuDas, M. R. et al. A consensus definitive classification of scavenger receptors and their roles in health and disease. J. Immunol. 198, 3775–3789 (2017).

    Article  CAS  PubMed  Google Scholar 

  33. 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  PubMed  CAS  Google Scholar 

  34. Tavukcuoglu, E. et al. Human splenic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are strategically located immune regulatory cells in cancer. Eur. J. Immunol. 50, 2067–2074 (2020).

    Article  CAS  PubMed  Google Scholar 

  35. Veglia, F., Perego, M. & Gabrilovich, D. I. Myeloid-derived suppressor cells coming of age. Nat. Immunol. 19, 108–119 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nan, J. et al. Endoplasmic reticulum stress induced LOX-1(+) CD15(+) polymorphonuclear myeloid-derived suppressor cells in hepatocellular carcinoma. Immunology 154, 144–155 (2018).

    Article  CAS  PubMed  Google Scholar 

  37. Abu-Raya, B., Michalski, C., Sadarangani, M. & Lavoie, P. M. Maternal immunological adaptation during normal pregnancy. Front. Immunol. 11, 575197 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rackaityte, E. & Halkias, J. Mechanisms of fetal T cell tolerance and immune regulation. Front. Immunol. 11, 588 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Miller, D. et al. Maternal and fetal T cells in term pregnancy and preterm labor. Cell. Mol. Immunol. 17, 693–704 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bezemer, R. E. et al. Altered levels of placental immune cell subsets in fetal growth restriction, stillbirth, and placental pathology. Front. Immunol. 11, 1898 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Li, Y. H. et al. The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal-fetal interface in early pregnancy. Cell. Mol. Immunol. 13, 73–81 (2016).

    Article  PubMed  CAS  Google Scholar 

  42. Dutta, S., Senguptaet, P. & Haque, N. Reproductive immunomodulatory functions of B cells in pregnancy. Int. Rev. Immunol. 39, 53–66 (2020).

    Article  CAS  PubMed  Google Scholar 

  43. Wang, S. C. et al. Programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) regulate CD4+ T cells to induce Type 2 helper T cell (Th2) bias at the maternal-fetal interface. Hum. Reprod. 31, 700–711 (2016).

    Article  CAS  PubMed  Google Scholar 

  44. Zhang, Y. H. et al. The altered PD-1/PD-L1 pathway delivers the ‘one-two punch’ effects to promote the Treg/Th17 imbalance in pre-eclampsia. Cell. Mol. Immunol. 15, 710–723 (2018).

    Article  CAS  PubMed  Google Scholar 

  45. Li, C. C. et al. Decidua-derived granulocyte macrophage colony-stimulating factor induces polymorphonuclear myeloid-derived suppressor cells from circulating CD15+ neutrophils. Hum. Reprod. 35, 2677–2691 (2020).

    Article  CAS  PubMed  Google Scholar 

  46. Miko, E. et al. Immune checkpoint molecules in reproductive immunology. Front. Immunol. 10, 846 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ghaebi, M. et al. Immune regulatory network in successful pregnancy and reproductive failures. Biomed. Pharmacother. 88, 61–73 (2017).

    Article  CAS  PubMed  Google Scholar 

  48. 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  PubMed  CAS  Google Scholar 

  49. Si, Y. et al. Multidimensional imaging provides evidence for down-regulation of T cell effector function by MDSC in human cancer tissue. Sci. Immunol. 4, eaaw9159 (2019).

    Article  CAS  PubMed  Google Scholar 

  50. Zhang, Y. et al. Human trophoblast cells induced MDSCs from peripheral blood CD14(+) myelomonocytic cells via elevated levels of CCL2. Cell. Mol. Immunol. 13, 615–627 (2016).

    Article  CAS  PubMed  Google Scholar 

  51. Ren, J. B. et al. Myeloid-derived suppressor cells depletion may cause pregnancy loss via upregulating the cytotoxicity of decidual natural killer cells. Am. J. Reprod. Immunol. 81, e13099 (2019).

    Article  PubMed  CAS  Google Scholar 

  52. 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  PubMed  CAS  Google Scholar 

  53. Lu, H. et al. Rapamycin prevents spontaneous abortion by triggering decidual stromal cell autophagy-mediated NK cell residence. Autophagy https://doi.org/10.1080/15548627.2020.1833515 (2020).

  54. Wang, Y. N. et al. Inhibition of pregnancy-associated granulocytic myeloid-derived suppressor cell expansion and arginase-1 production in preeclampsia. J. Reprod. Immunol. 127, 48–54 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Fu, B. Q., Tian, Z. G. & Wei, H. M. TH17 cells in human recurrent pregnancy loss and pre-eclampsia. Cell. Mol. Immunol. 11, 564–570 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang, S. C. et al. PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy. Cell. Death. Dis. 6, e1738 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ding, H. L. et al. Upregulation of CD81 in trophoblasts induces an imbalance of Treg/Th17 cells by promoting IL-6 expression in preeclampsia. Cell. Mol. Immunol. 16, 302–312 (2019).

    Article  PubMed  CAS  Google Scholar 

  58. Sharma, D., Farahbakhsh, N., Shastri, S. & Sharma, P. Intrauterine growth restriction—part 2. J. Matern. Fetal Neonatal Med. 29, 4037–4048 (2016).

    Article  PubMed  Google Scholar 

  59. Saleem, T. et al. Intrauterine growth retardation–small events, big consequences. Ital. J. Pediatr. 37, 41 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Sacchi, C. et al. Association of intrauterine growth restriction and small for gestational age status with childhood cognitive outcomes: a systematic review and meta-analysis. Jama. Pediatr. 174, 772–781 (2020).

    Article  PubMed  Google Scholar 

  61. Lager, S. et al. Abnormal placental CD8(+) T-cell infiltration is a feature of fetal growth restriction and pre-eclampsia. J. Physiol. 598, 5555–5571 (2020).

    Article  CAS  PubMed  Google Scholar 

  62. Lin, F. et al. The maternal-fetal interface in small-for-gestational-age pregnancies is associated with a reduced quantity of human placental NK cells with weaker functional ability. Front. Cell. Dev. Biol. 8, 633 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Wang, H. K. et al. The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells. Nat. Immunol. 15, 667–675 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sidwell, T. et al. Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis. Nat. Commun. 11, 252 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sarhan, D. et al. Adaptive NK cells with low TIGIT expression are inherently resistant to myeloid-derived suppressor cells. Cancer Res. 76, 5696–5706 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Steggerda, S. M. et al. Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J. Immunother. Cancer 5, 101 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Heine, A. et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 122, 1192–1202 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Ugolini, A. et al. Polymorphonuclear myeloid-derived suppressor cells limit antigen cross-presentation by dendritic cells in cancer. Jci. Insight 5, e138581 (2020).

    Article  PubMed Central  Google Scholar 

  69. Zhang, Z. et al. Intrauterine growth restriction programs intergenerational transmission of pulmonary arterial hypertension and endothelial dysfunction via sperm epigenetic modifications. Hypertension 74, 1160–1171 (2019).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the following institutions: the High-level Talent Start-up Funding of Southern Medical University, the National Natural Science Foundation of China (grant numbers: 31700061, 81971420 and 81991511), the Guangdong Special Support Program for Youth Science and Technology Innovation Talents (grant number: 2019TQ05Y585), the National Natural Science Foundation of Guangdong (grant number: 2019A1515011435), and the Science and Technology Program of Guangzhou (grant number: 201904010073).

Author information

Author notes

  1. These authors contributed equally: Mengyu Shi, Ziyang Chen, Meiqi Chen, Jingping Liu

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Mengyu Shi, Ziyang Chen, Meiqi Chen, Zhe Xing, Xiaogang Zhang, Shuaijun Lv, Xinyao Li, Shaowen Zuo, Shi Feng, Ying Lin & Yumei He

  2. Department of Laboratory Medicine, the Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China

    Jingping Liu, Gang Xiao & Yumei He

  3. Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Jing Li

  4. The First Affiliated Hospital of Shenzhen University, Reproductive Medicine Centre, Shenzhen Second People’s Hospital, Shenzhen, China

    Liping Wang

  5. Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    Yumei He

  6. Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China

    Yumei He

Authors
  1. Mengyu Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ziyang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meiqi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jingping Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhe Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaogang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shuaijun Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xinyao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shaowen Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shi Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ying Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gang Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Liping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yumei He
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.H., L.W., and G.X. designed the study. M.S., Z.C., M.C., J.L., J.L., Z.X., X.Z., S.L., X.L., S.Z., S.F., and Y.L. performed the experiments in this study. Y.H., L.W., and G.X. wrote the paper. All authors contributed to the discussion of the study and revision of the paper.

Corresponding authors

Correspondence to Gang Xiao, Liping Wang or Yumei He.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, M., Chen, Z., Chen, M. et al. Continuous activation of polymorphonuclear myeloid-derived suppressor cells during pregnancy is critical for fetal development. Cell Mol Immunol 18, 1692–1707 (2021). https://doi.org/10.1038/s41423-021-00704-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-021-00704-w

Keywords

This article is cited by

Search

Advanced search

Quick links