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Academic Journal of Medicine & Health Sciences, 2023, 4(3); doi: 10.25236/AJMHS.2023.040302.

Research progress in the mechanism of action of NK cell-related receptors during recurrent spontaneous abortion


Yuan Rougang1, Zhao Xiaoli1, Zhang Xinwen2

Corresponding Author:
Zhang Xinwen

1Second Clinical Medical College of Shaanxi University of Chinese Medicine, Xi'an, Shaanxi, 712046, China

2Women's Health Center of Xi'an People's Hospital/Xi'an Fourth Hospital, Xi'an, Shaanxi, 710004, China


Recurrent spontaneous abortion (RSA) refers to multiple spontaneous abortions with the same sexual partner; In 2020, Chinese expert consensus suggested that it should be defined as the loss of the embryo or fetus before 28 weeks of gestation with the same sexual partner for two or more times in a row, including the biochemical pregnancy that occurred several times in a row. The pathogenesis of RSA is complex and diverse. At present, the pathogenesis factors have been widely recognized by the industry, including genetic factors, endocrine factors, anatomical abnormalities, infectious factors and immune factors. Among them, the role of immune factors such as T lymphocytes, dendritic cells and natural killer cells (NK) in the occurrence and development of RSA has attracted wide attention, especially NK cells. NK cells are an important part of human immune system. The specific surface molecules of Decidual natural killer cell (dNK) play an immunomodulatory role in the invasion of trophoblast cells and the remodeling of uterine spiral artery during pregnancy, which is particularly important in the early gestation period. The function of dNK cells is tightly regulated by a balance between activation and inhibition signals transmitted by the various family of receptors (NK cell receptors, NKRS) that DNK cells express. In this paper, the existing research progress of decidual NK cells on the mechanism of its receptors in the process of recurrent spontaneous abortion will be reviewed as follows.


Recurrent spontaneous abortion; Decidual natural killer cells; Receptors

Cite This Paper

Yuan Rougang, Zhao Xiaoli, Zhang Xinwen. Research progress in the mechanism of action of NK cell-related receptors during recurrent spontaneous abortion. Academic Journal of Medicine & Health Sciences (2023) Vol. 4, Issue 3: 8-14. https://doi.org/10.25236/AJMHS.2023.040302.


[1] Croy BA., He H, Esadeg S. (2003) Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling. Reproduction, 2, 149-160. 

[2] EB ASH., AMA., (2020) Concordance between peripheral and decidual NK cell subsets and killer immunoglobulin-like receptors in women with recurrent spontaneous miscarriages. J reprod immunol, 1, 103-130. 

[3] Xie M., Li Y., Meng YZ. (2022)Uterine Natural Killer Cells:a rising star in human pregnancy regulation. Front Immunol, 13, 918550. 

[4] H Lu., L Jin., H Huang. (2020) Trophoblast-derived CXCL12 promotes CD56(bright) CD82(-) CD29(+) NK cell enrichment in the decidua. Am J Reprod Immunol, 83, e13203. 

[5] Ran GH., Lin YQ., Tian L. (2022) Natural killer cell homing and trafficking in tissues and tumors: from biology to application. Signal Transduct Target Ther, 7, 205-205. 

[6] Varla-Leftherioti M., Keramitsoglou T. (2016) Natural killer (NK) cell receptors and their role in pregnancy and abortion. J Immunobiol, 1, 1-6. 

[7] Feyaerts D., Kuret T., Van Cranenbroek B. (2018)Endometrial natural killer (NK) cells reveal a tissue-specific receptor repertoire. Hum Reprod, 33, 441-451. 

[8] Colucci F. (2017) The role of KIR and HLA interactions in pregnancy complications. Immunogenetics, 69, 557-565. 

[9] Gao F., Ye Y., Gao Y. (2020) Influence of KIR and NK Cell Reconstitution in the Outcomes of Hematopoietic Stem Cell Transplantation. Front Immunol, 11, 2022-2022. 

[10] Diaz-Pena R., de Los S M., Lucia A. (2019) Understanding the role of killer cell immunoglobulin-like receptors in pregnancy complications. J Assist Reprod Genet, 36, 827-835. 

[11] Akbari S., Shahsavar F., Karami R. (2020) Recurrent Spontaneous Abortion (RSA) and Maternal KIR Genes: A Comprehensive Meta-Analysis. JBRA Assist Reprod, 24, 197-213. 

[12] Kniotek M., Roszczyk A., Zych M. (2021) Differences in the Expression of KIR, ILT Inhibitory Receptors, and VEGF Production in the Induced Decidual NK Cell Cultures of Fertile and RPL Women. Biomed Res Int, 5, 1-10. 

[13] Liu Y., Gao S., Zhao Y. (2021) Decidual Natural Killer Cells: A Good Nanny at the Maternal-Fetal Interface During Early Pregnancy. Front Immunol, 12, 151-168. 

[14] Deng Z., Zhen J., Harrison G F. (2021) Adaptive Admixture of HLA class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians. Molecular biology and evolution, 6, 2582-2596. 

[15] Debska-Zielkowska J., Moszkowska G., Zielinski M. (2021) KIR Receptors as Key Regulators of NK Cells Activity in Health and Disease. Cells, 10, 1777-1777. 

[16] Su N., Wang H., Zhang B. (2018) Maternal natural killer cell immunoglobulin receptor genes and human leukocyte antigen-C ligands influence recurrent spontaneous abortion in the Han Chinese population. Exp Ther Med, 1, 327-337. 

[17] Ning S., Hongdan W., Bowei Z. (2018) Maternal natural killer cell immunoglobulin receptor genes and human leukocyte antigen-C ligands influence recurrent spontaneous abortion in the Han Chinese population. Experimental and therapeutic medicine, 15, 327-337. 

[18] Hui Yihua, Wang Haina., Su Wen. (2020) Research progress on the expression profile and function of Natural killer (NK) cell surface receptors. Journal of Cell and Molecular Immunology, 8, 740-744. 

[19] Shmeleva EV., Colucci F. (2021) Maternal natural killer cells at the intersection between reproduction and mucosal immunity. Mucosal Immunol, 5, 991-1005. 

[20] Hanna J., Goldman-Wohl D., Hamani Y. (2006) Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nature Medicine, 12, 1065-1074. 

[21] Luczo JM., Ronzulli SL., Tompkins SM. (2021) Influenza A Virus Hemagglutinin and Other Pathogen Glycoprotein Interactions with NK Cell Natural Cytotoxicity Receptors NKp46, NKp44, and NKp30. Viruses, 13, 156. 

[22] Siewiera J., Gouilly J., Hocine H. (2015) Natural cytotoxicity receptor splice variants orchestrate the distinct functions of human natural killer cell subtypes[J]. Nature Communications, 6, 10183. 

[23] Yamamoto M., Fukui A., Mai C. (2022) Evaluation of NKp46 expression and cytokine production of decidual NK cells in women with recurrent pregnancy loss. Reprod Med Biol, 21, e12478-e12478. 

[24] Atsushi F., Ayano F., Rie F. (2017)Expression of natural cytotoxicity receptors and cytokine production on endometrial natural killer cells in women with recurrent pregnancy loss or implantation failure, and the expression of natural cytotoxicity receptors on peripheral blood natural killer cells in pregnant women with a history of recurrent pregnancy loss. J Obstet Gynaecol Res, 8, 1678-1686. 

[25] Mai C., Fukui A., Takeyama R. (2021)NK cells that differ in expression of NKp46 might play different roles in endometrium. J Reprod Immunol, 9, 103367-103367. 

[26] Feifei Z., Junke Z., Xunlei K. (2015) Inhibitory leukocyte immunoglobulin-like receptors in cancer development. Sci China Life Sci, 11, 1216-1225. 

[27] Xu X., Zhou Y., Wei H. (2020)Roles of HLA-G in the Maternal-Fetal Immune Microenvironment. Front Immunol, 11, 592010-592010. 

[28] Nowak I., Wilczyńska K., Wilczyński J R. (2017)KIR, LILRB and their Ligands’ Genes as Potential Biomarkers in Recurrent Implantation Failure. Arch Immunol Ther Exp, 10, 391-399. 

[29] Shreeve N., Depierreux D., Hawkes D. (2021) The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice. Immunity, 6, 1231-1244. 

[30] GBA., FB., EPP. (1999)Specific recognition of HLA-E, but not classical, HLA class I molecules by soluble CD94/NKG2A and NK cells. J Immunol, 1, 305-313. 

[31] Wang Y. (2002)Inhibitory receptor of CD94/NKG2A-C type lectin superfamily. Journal of Chinese Academy of Medical Sciences, 6, 653-655. 

[32] Colucci F. (2022) Uterine NK Cells Ace an "A" in Education: NKG2A Sets Up Crucial Functions at the Maternal-Fetal Interface. J Immunol, 8, 1421-1425. 

[33] Xie M., Li Y., Meng YZ. (2022)Uterine Natural Killer Cells: A Rising Star in Human Pregnancy Regulation. Front Immunol, 13, 918550. 

[34] Jones AB., Rocco A., Lamb L S. Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression. Cancers (Basel), 14, 2339-2339. 

[35] Zhang J., Dunk CE., Kwan M. (2017)Human dNK cell function is differentially regulated by extrinsic cellular engagement and intrinsic activating receptors in first and second trimester pregnancy. Cell Mol Immunol, 14, 203-213. 

[36] Fan J., Shi J, Zhang Y. (2022) NKG2D discriminates diverse ligands through selectively mechano-regulated ligand conformational changes. EMBO J, 2, e107739-e107739. 

[37] Alves E., Mcleish E., Blancafort P. (2017) Manipulating the NKG2D Receptor-Ligand Axis Using CRISPR: Novel Technologies for Improved Host Immunity. Front Immunol, 12, 3263-3263. 

[38] Emanuele G., Marina C., Toshiyuki T. (2007) Phosphatidylinositol 3-kinase activation is required to form the NKG2D immunological synapse. Mol Cell Biol, 24, 8583-8599. 

[39] Mincheva-Nilsson. (2010)Placental exosome-mediated immune protection of the fetus: feeling groovy in a cloud of exosomes. Expert Rev Obstet Gynecol, 5, 619-634. 

[40] Burkova EE., Sedykh SE., Nevinsky GA. (2021) Human Placenta Exosomes: Biogenesis, Isolation, Composition, and Prospects for Use in Diagnostics. Int J Mol Sci, 22, 2158-2158. 

[41] Mei B., Zhang S., Chen Y. (2012) Defects in NKG2D ligand expression result in failed tolerance induction at the maternal–fetal interface: A possible cause for recurrent miscarriage. Med Hypotheses, 4, 465-467. 

[42] Sondes H., Nabil M., Safia M. (2014) Polymorphisms in genes coding for the NK-cell receptor NKG2D and its ligand MICA in recurrent miscarriage. Am J Reprod Immunol, 6, 577-585.