Skip to main content

Advertisement

SpringerLink
Log in

Exploring Natural Killer Cell Testing in Embryo Implantation and Reproductive Failure: An Overview of Techniques and Controversies

  • Embryology: Review
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The blastocyst nidation is the most crucial stage to a successful pregnancy, as the white cells work to promote a favorable endometrial microenvironment for this process. Intriguingly, this implantation window lasts, on average, 6 days in most regular women, and its quality is affected by many pathological conditions. Since the grounds of reproductive failure in healthy couples are still uncharted, studies have widely suggested a potential hostile role of the immune system in the equilibrium of the maternal–fetal interface. In recent years, natural killer cells have been the highlight as they represent the greatest lymphocyte in the uterus and have immune surveillance through cytotoxicity during the implantation window. This review explored the main techniques used for natural killer (NK) cell testing in the implantation window over the last 13 years on the PubMed® database. Of 2167 published articles potentially relevant for the review, only thirty-three were about cell evaluation in healthy women, met the inclusion criteria, and had their methodology critically analyzed. Here, we bring a summary from the study group and sample collection to evidence comments about their findings and correlations. Meanwhile, we also summarize the current relationship between NK cells and endometrial receptivity with reproductive failure to help enhance the possibilities for future research. In conclusion, our overview points out that restricted and unstandardized methods support the controversy between the NK population and unsuccessful embryo implantation, which is an obstacle to studying why healthy eggs do not thrive and finding a solution for one of the most controversial topics in human reproduction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

The data supporting this study's findings are available in the public domain and were derived from the PubMed library.

References

  1. Muter J, Lynch VJ, McCoy RC, Brosens JJ. Human embryo implantation. Dev. 2023;150(10):dev201507. https://doi.org/10.1242/dev.201507. 

    Article  CAS  Google Scholar 

  2. Ma J, Gao W, Li D. Recurrent implantation failure: a comprehensive summary from etiology to treatment. Front Endocrinol (Lausanne). 2023;5(13):1061766. https://doi.org/10.3389/fendo.2022.1061766.

    Article  Google Scholar 

  3. Lessey BA, Young SL. What exactly is endometrial receptivity? Fertil Steril. 2019;111(4):611–7. https://doi.org/10.1016/j.fertnstert.2019.02.009. 

    Article  PubMed  Google Scholar 

  4. Zhang H, Huang C, Chen X, Li L, Liu S, Li Y, Zhang Y, Zeng Y, Hu L. The number, cytotoxicity, and the expression of cytotoxicity-related molecules in peripheral natural killer (NK) cells do not predict repeated implantation failure (RIF) in the in vitro fertilization patients. Genes Dis. 2019;7(2):283–9. https://doi.org/10.1016/j.gendis.2019.03.005.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Moffett A, Shreeve N. Local immune recognition of trophoblast in early human pregnancy: controversies and questions. Nat Rev Immunol. 2023;23(4):222–35. https://doi.org/10.1038/s41577-022-00777-2. 

    Article  CAS  PubMed  Google Scholar 

  6. Pierce S, Geanes ES, Bradley T. Targeting natural killer cells for improved immunity and control of the adaptive immune response. Front Cell Infect Microbiol. 2020;19(10):231. https://doi.org/10.3389/fcimb.2020.00231.

    Article  Google Scholar 

  7. Marron K, Harrity C. Endometrial lymphocyte concentrations in adverse reproductive outcome populations. J Assist Reprod Genet. 2019;36(5):837–46. https://doi.org/10.1007/s10815-019-01427-8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Massri N, Loia R, Sones JL, Arora R, Douglas NC. Vascular changes in the cycling and early pregnant uterus. JCI Insight. 2023;8(11): e163422. https://doi.org/10.1172/jci.insight.163422.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Tohma YA, Musabak U, Gunakan E, Akilli H, Onalan G, Zeyneloglu HB. The role of analysis of NK cell subsets in peripheral blood and uterine lavage samples in evaluation of patients with recurrent implantation failure. J Gynecol Obstet Hum Reprod. 2020;49(9):101793. https://doi.org/10.1016/j.jogoh.2020.101793. 

    Article  PubMed  Google Scholar 

  10. Sojka DK, Yang L, Yokoyama WM. Uterine natural killer cells Front Immunol. 2019;1(10):960. https://doi.org/10.3389/fimmu.2019.00960.

    Article  Google Scholar 

  11. Wei XW, Zhang YC, Wu F, Tian FJ, Lin Y. The role of extravillous trophoblasts and uterine NK cells in vascular remodeling during pregnancy. Front Immunol. 2022Jul;22(13): 951482. https://doi.org/10.3389/fimmu.2022.951482.

    Article  Google Scholar 

  12. Wolf K, Ibrahim SA, Schneiderman S, Riehl V, Dambaeva S, Beaman K. Conventional natural killer cells control vascular remodeling in the uterus during pregnancy by acidifying the extracellular matrix with a2V. Biol Reprod. 2023;108(1):121–32. https://doi.org/10.1093/biolre/ioac184.

    Article  PubMed  Google Scholar 

  13. Sauerbrun-Cutler MT, Huber WJ, Krueger PM, Sung CJ, Has P, Sharma S. Do endometrial natural killer and regulatory T cells differ in infertile and clinical pregnancy patients? An analysis in patients undergoing frozen embryo transfer cycles. Am J Reprod Immunol. 2021;85(6):e13393. https://doi.org/10.1111/aji.13393. 

    Article  CAS  PubMed  Google Scholar 

  14. Vacca P, Moretta L, Moretta A, Mingari MC. Origin, phenotype and function of human natural killer cells in pregnancy. Trends Immunol. 2011;32(11):517–23. https://doi.org/10.1016/j.it.2011.06.013. 

    Article  CAS  PubMed  Google Scholar 

  15. Donoghue JF, Paiva P, Teh WT, Cann LM, Nowell C, Rees H, Bittinger S, Obers V, Bulmer JN, Stern C, McBain J, Rogers PAW. Endometrial uNK cell counts do not predict successful implantation in an IVF population. Hum Reprod. 2019;34(12):2456–66. https://doi.org/10.1093/humrep/dez194. 

    Article  CAS  PubMed  Google Scholar 

  16. Bulmer JN, Innes BA, Robson SC, Lash GE. Transient loss of endothelial cells in human spiral artery remodelling during early pregnancy: challenging the dogma. Placenta. 2020;101:230–3. https://doi.org/10.1016/j.placenta.2020.10.003. 

    Article  PubMed  Google Scholar 

  17. Robson A, Lash GE, Innes BA, Zhang JY, Robson SC, Bulmer JN. Uterine spiral artery muscle dedifferentiation. Hum Reprod. 2019;34(8):1428–38. https://doi.org/10.1093/humrep/dez124. 

    Article  CAS  PubMed  Google Scholar 

  18. Huhn O, Zhao X, Esposito L, Moffett A, Colucci F, Sharkey AM. How do uterine natural killer and innate lymphoid cells contribute to successful pregnancy? Front Immunol. 2021;21(12): 607669. https://doi.org/10.3389/fimmu.2021.607669.

    Article  Google Scholar 

  19. Zhang X, Wei H. Role of decidual natural killer cells in human pregnancy and related pregnancy complications. Front Immunol. 2021;26(12): 728291. https://doi.org/10.3389/fimmu.2021.728291.

    Article  Google Scholar 

  20. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. Front Immunol. 2019;7(10):909. https://doi.org/10.3389/fimmu.2019.00909.

    Article  Google Scholar 

  21. Cerdeira AS, Rajakumar A, Royle CM, Lo A, Husain Z, Thadhani RI, Sukhatme VP, Karumanchi SA, Kopcow HD. Conversion of peripheral blood NK cells to a decidual NK-like phenotype by a cocktail of defined factors. J Immunol. 2013;190(8):3939–48. https://doi.org/10.4049/jimmunol.1202582. 

    Article  CAS  PubMed  Google Scholar 

  22. Whettlock EM, Woon EV, Cuff AO, Browne B, Johnson MR, Male V. Dynamic changes in uterine NK cell subset frequency and function over the menstrual cycle and pregnancy. Front Immunol. 2022;16(13): 880438. https://doi.org/10.3389/fimmu.2022.880438.

    Article  Google Scholar 

  23. Papúchová H, Meissner TB, Li Q, Strominger JL, Tilburgs T. The dual role of HLA-C in tolerance and immunity at the maternal-fetal interface. Front Immunol. 2019;9(10):2730. https://doi.org/10.3389/fimmu.2019.02730.

    Article  Google Scholar 

  24. Xu X, Zhou Y, Wei H. Roles of HLA-G in the maternal-fetal immune microenvironment. Front Immunol. 2020;22(11): 592010. https://doi.org/10.3389/fimmu.2020.592010.

    Article  Google Scholar 

  25. Nakashima A, Shima T, Inada K, Ito M, Saito S. The balance of the immune system between T cells and NK cells in miscarriage. Am J Reprod Immunol. 2012;67(4):304–10. https://doi.org/10.1111/j.1600-0897.2012.01115.x.

    Article  CAS  PubMed  Google Scholar 

  26. Male V, Moffett A. Natural killer cells in the human uterine mucosa. Annu Rev Immunol. 2023;26(41):127–51. https://doi.org/10.1146/annurev-immunol-102119-075119.

    Article  CAS  Google Scholar 

  27. Zhang Y, Huang C, Lian R, Xu J, Fu Y, Zeng Y, Tu W. The low cytotoxic activity of peripheral blood NK cells may relate to unexplained recurrent miscarriage. Am J Reprod Immunol. 2021;85(6):e13388. https://doi.org/10.1111/aji.13388. 

    Article  CAS  PubMed  Google Scholar 

  28. Mahajan D, Sharma NR, Kancharla S, Kolli P, Tripathy A, Sharma AK, Singh S, Kumar S, Mohanty AK, Jena MK. Role of natural killer cells during pregnancy and related complications. Biomolecules. 2022;12(1):68. https://doi.org/10.3390/biom12010068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chang RQ, Zhou WJ, Li DJ, Li MQ. Innate lymphoid cells at the maternal-fetal interface in human pregnancy. Int J Biol Sci. 2020;16(6):957–69. https://doi.org/10.7150/ijbs.38264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li H, Hou Y, Zhang S, Zhou Y, Wang D, Tao S, Ni F. CD49a regulates the function of human decidual natural killer cells. Am J Reprod Immunol. 2019;81(4):e13101. https://doi.org/10.1111/aji.13101. 

    Article  CAS  PubMed  Google Scholar 

  31. Cavalcante MB, da Silva PHA, Carvalho TR, Sampaio OGM, Câmara FEA, Cavalcante CTMB, Barini R, Kwak-Kim J. Peripheral blood natural killer cell cytotoxicity in recurrent miscarriage: a systematic review and meta-analysis. J Reprod Immunol. 2023;18(158):103956. https://doi.org/10.1016/j.jri.2023.103956. 

    Article  CAS  Google Scholar 

  32. Strunz B, Bister J, Jönsson H, Filipovic I, Crona-Guterstam Y, Kvedaraite E, Sleiers N, Dumitrescu B, Brännström M, Lentini A, Reinius B, Cornillet M, Willinger T, Gidlöf S, Hamilton RS, Ivarsson MA, Björkström NK. Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy. Sci Immunol. 2021;6(56):eabb7800. https://doi.org/10.1126/sciimmunol.abb7800. 

    Article  CAS  PubMed  Google Scholar 

  33. El-Badawy O, Helmy AS, Abbas AM, Zahran AM, Afifi NA, Abdel-Rahim MH. Concordance between peripheral and decidual NK cell subsets and killer immunoglobulin-like receptors in women with recurrent spontaneous miscarriages. J Reprod Immunol. 2020;140: 103130. https://doi.org/10.1016/j.jri.2020.103130. 

    Article  CAS  PubMed  Google Scholar 

  34. Kwak-Kim J, AlSubki L, Luu T, Ganieva U, Thees A, Dambaeva S, Gilman-Sachs A. The role of immunologic tests for subfertility in the clinical environment. Fertil Steril. 2022;117(6):1132–43. https://doi.org/10.1016/j.fertnstert.2022.04.009. 

    Article  CAS  PubMed  Google Scholar 

  35. Kolanska K, Suner L, Cohen J, Ben Kraiem Y, Placais L, Fain O, Bornes M, Selleret L, Delhommeau F, Feger F, Mathieu d’Argent E, Darai E, Chabbert-Buffet N, Antoine JM, Kayem G, Mekinian A. Proportion of cytotoxic peripheral blood natural killer cells and T-cell large granular lymphocytes in recurrent miscarriage and repeated implantation failure: case-control study and meta-analysis. Arch Immunol Ther Exp (Warsz). 2019;67(4):225–36. https://doi.org/10.1007/s00005-019-00546-5.

    Article  CAS  PubMed  Google Scholar 

  36. Koot YEM, Teklenburg G, Salker MS, Brosens JJ, Macklon NS. Molecular aspects of implantation failure. Biochim Biophys Acta. 2012;1822(12):1943–50.

    Article  CAS  PubMed  Google Scholar 

  37. Marron K, Walsh D, Harrity C. Detailed endometrial immune assessment of both normal and adverse reproductive outcome populations. J Assist Reprod Genet. 2019;36(2):199–210. https://doi.org/10.1007/s10815-018-1300-8. 

    Article  PubMed  Google Scholar 

  38. Franasiak JM, Scott RT. Contribution of immunology to implantation failure of euploid embryos. Fertil Steril. 2017;107(6):1279–83. https://doi.org/10.1016/j.fertnstert.2017.04.019. 

    Article  CAS  PubMed  Google Scholar 

  39. Nielsen CM, White MJ, Goodier MR, Riley EM. Functional significance of CD57 expression on human NK cells and relevance to disease. Front Immunol. 2013;9(4):422. https://doi.org/10.3389/fimmu.2013.00422.

    Article  Google Scholar 

  40. Boyson JE, Aktan I, Barkhuff DA, Chant A. NKT cells at the maternal-fetal interface. Immunol Invest. 2008;37(5):565–82. https://doi.org/10.1080/08820130802191409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zarobkiewicz MK, Morawska I, Michalski A, Roliński J, Bojarska-Junak A. NKT and NKT-like cells in autoimmune neuroinflammatory diseases-multiple sclerosis, myasthenia gravis and Guillain-Barre syndrome. Int J Mol Sci. 2021;22(17):9520. https://doi.org/10.3390/ijms22179520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kronenberg M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol. 2005;23:877–900. https://doi.org/10.1146/annurev.immunol.23.021704.115742.

    Article  CAS  PubMed  Google Scholar 

  43. Yuan J, Li J, Huang SY, Sun X. Characterization of the subsets of human NKT-like cells and the expression of Th1/Th2 cytokines in patients with unexplained recurrent spontaneous abortion. J Reprod Immunol. 2015;110:81–8. https://doi.org/10.1016/j.jri.2015.05.001.

    Article  CAS  PubMed  Google Scholar 

  44. Miko E, Barakonyi A, Meggyes M, Szereday L. The role of type I and type II NKT cells in materno-fetal immunity. Biomedicines. 2021;9(12):1901. https://doi.org/10.3390/biomedicines9121901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yüzen D, Arck PC, Thiele K. Tissue-resident immunity in the female and male reproductive tract. Semin Immunopathol. 2022;44(6):785–99. https://doi.org/10.1007/s00281-022-00934-8.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Meggyes M, Miko E, Szigeti B, Farkas N, Szereday L. The importance of the PD-1/PD-L1 pathway at the maternal-fetal interface. BMC Pregnancy Childbirth. 2019;19(1):74. https://doi.org/10.1186/s12884-019-2218-6.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Markel G, Wolf D, Hanna J, Gazit R, Goldman-Wohl D, Lavy Y, Yagel S, Mandelboim O. Pivotal role of CEACAM1 protein in the inhibition of activated decidual lymphocyte functions. J Clin Invest. 2002;110(7):943–53. https://doi.org/10.1172/JCI15643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ito K, Karasawa M, Kawano T, Akasaka T, Koseki H, Akutsu Y, Kondo E, Sekiya S, Sekikawa K, Harada M, Yamashita M, Nakayama T, Taniguchi M. Involvement of decidual Valpha14 NKT cells in abortion. Proc Natl Acad Sci U S A. 2000;97(2):740–4. https://doi.org/10.1073/pnas.97.2.740.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. Khalaf WS, Mahmoud MRA, Elkhatib WF, Hashem HR, Soliman WE. Phenotypic characterization of NKT-like cells and evaluation of specifically related cytokines for the prediction of unexplained recurrent miscarriage. Heliyon. 2021;7(11): e08409. https://doi.org/10.1016/j.heliyon.2021.e08409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Comins-Boo A, Cristóbal I, Fernández-Arquero M, Rodríguez de Frías E, Calvo Urrutia M, Pilar Suárez L, Gasca Escorial P, Ángel Herráiz M, Sánchez-Ramón S. Functional NK surrogate biomarkers for inflammatory recurrent pregnancy loss and recurrent implantation failure. Am J Reprod Immunol. 2021;86(2):13426. https://doi.org/10.1111/aji.13426.

    Article  CAS  Google Scholar 

  51. Zhang J, Dunk CE, Shynlova O, Caniggia I, Lye SJ. TGFb1 suppresses the activation of distinct dNK subpopulations in preeclampsia. EBioMedicine. 2019;39:531–9. https://doi.org/10.1016/j.ebiom.2018.12.015.

    Article  PubMed  Google Scholar 

  52. El Costa H, Casemayou A, Aguerre-Girr M, Rabot M, Berrebi A, Parant O, Clouet-Delannoy M, Lombardelli L, Jabrane-Ferrat N, Rukavina D, Bensussan A, Piccinni MP, Le Bouteiller P, Tabiasco J. Critical and differential roles of NKp46- and NKp30-activating receptors expressed by uterine NK cells in early pregnancy. J Immunol. 2008;181(5):3009–17. https://doi.org/10.4049/jimmunol.181.5.3009. 

    Article  PubMed  Google Scholar 

  53. Delahaye NF, Rusakiewicz S, Martins I, Ménard C, Roux S, Lyonnet L, Paul P, Sarabi M, Chaput N, Semeraro M, Minard-Colin V, Poirier-Colame V, Chaba K, Flament C, Baud V, Authier H, Kerdine-Römer S, Pallardy M, Cremer I, Peaudecerf L, Rocha B, Valteau-Couanet D, Gutierrez JC, Nunès JA, Commo F, Bonvalot S, Ibrahim N, Terrier P, Opolon P, Bottino C, Moretta A, Tavernier J, Rihet P, Coindre JM, Blay JY, Isambert N, Emile JF, Vivier E, Lecesne A, Kroemer G, Zitvogel L. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med. 2011;17(6):700–7. https://doi.org/10.1038/nm.2366. 

    Article  CAS  PubMed  Google Scholar 

  54. Siewiera J, Gouilly J, Hocine HR, Cartron G, Levy C, Al-Daccak R, Jabrane-Ferrat N. Natural cytotoxicity receptor splice variants orchestrate the distinct functions of human natural killer cell subtypes. Nat Commun. 2015;15(6):10183. https://doi.org/10.1038/ncomms10183.

    Article  Google Scholar 

  55. Hromadnikova I, Pirkova P, Sedlackova L. Influence of in vitro IL-2 or IL-15 alone or in combination with Hsp-70-derived 14-mer peptide (TKD) on the expression of NK cell activatory and inhibitory receptors. Mediators Inflamm. 2013;2013:405295. https://doi.org/10.1155/2013/405295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cella M, Miller H, Song C. Beyond NK cells: the expanding universe of innate lymphoid cells. Front Immunol. 2014;16(5):282. https://doi.org/10.3389/fimmu.2014.00282.

    Article  Google Scholar 

  57. Barrow AD, Edeling MA, Trifonov V, Luo J, Goyal P, Bohl B, Bando JK, Kim AH, Walker J, Andahazy M, Bugatti M, Melocchi L, Vermi W, Fremont DH, Cox S, Cella M, Schmedt C, Colonna M. Natural killer cells control tumor growth by sensing a growth factor. Cell. 2018;172(3):534-548.e19. https://doi.org/10.1016/j.cell.2017.11.037. 

    Article  CAS  PubMed  Google Scholar 

  58. Marrufo AM, Mathew SO, Chaudhary P, Malaer JD, Ahmed N, Vishwanatha JK, Mathew PA. Blocking PCNA interaction with NKp44 enhances primary natural killer cell-mediated lysis of triple-negative breast cancer cells. Am J Cancer Res. 2023;13(3):1082–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Korgun ET, Celik-Ozenci C, Acar N, Cayli S, Desoye G, Demir R. Location of cell cycle regulators cyclin B1, cyclin A, PCNA, Ki67 and cell cycle inhibitors p21, p27 and p57 in human first trimester placenta and deciduas. Histochem Cell Biol. 2006Jun;125(6):615–24. https://doi.org/10.1007/s00418-006-0160-y. 

    Article  CAS  PubMed  Google Scholar 

  60. Fukui A, Funamizu A, Fukuhara R, Shibahara H. 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. 2017;43(11):1678–86. https://doi.org/10.1111/jog.13448. 

    Article  CAS  PubMed  Google Scholar 

  61. Dons’koi BV, Osypchuk DV, Chernyshov VP. Enumeration of peripheral blood NKp46 positive NK lymphocytes reflects NK cytotoxic activity in vitro. J Immunol Methods. 2019;474:112639. https://doi.org/10.1016/j.jim.2019.112639. 

    Article  CAS  PubMed  Google Scholar 

  62. Barry F, Benart L, Robert L, Gala A, Ferrières-Hoa A, Loup V, Anahory T, Brouillet S, Hamamah S. Interactions HLA-C KIR et anomalies de la placentation : implications dans les issues de grossesses obtenues en AMP [HLA-C KIR interactions and placental defects: Implications in ART pregnancy issues]. Gynecol Obstet Fertil Senol. 2022;50(9):600–9. https://doi.org/10.1016/j.gofs.2022.06.003. 

    Article  CAS  PubMed  Google Scholar 

  63. Huang C, Zhang Y, Xiang Z, Li Y, Lin R, Xu J, Tu W, Zeng Y. Granzyme B-expressing γδ-T and NK cells as a predictor of clinical pregnancy failure in patients with unexplained repeated implantation failure. J Reprod Immunol. 2021;144: 103269. https://doi.org/10.1016/j.jri.2020.103269.

    Article  CAS  PubMed  Google Scholar 

  64. Hiby SE, Apps R, Chazara O, Farrell LE, Magnus P, Trogstad L, Gjessing HK, Carrington M, Moffett A. Maternal KIR in combination with paternal HLA-C2 regulate human birth weight. J Immunol. 2014;192(11):5069–73. https://doi.org/10.4049/jimmunol.1400577. 

    Article  CAS  PubMed  Google Scholar 

  65. Morin SJ, Treff NR, Tao X, Scott RT 3rd, Franasiak JM, Juneau CR, Maguire M, Scott RT. Combination of uterine natural killer cell immunoglobulin receptor haplotype and trophoblastic HLA-C ligand influences the risk of pregnancy loss: a retrospective cohort analysis of direct embryo genotyping data from euploid transfers. Fertil Steril. 2017;107(3):677-683.e2. https://doi.org/10.1016/j.fertnstert.2016.12.004. 

    Article  CAS  PubMed  Google Scholar 

  66. Stefańska K, Tomaszewicz M, Dębska-Zielkowska J, Zamkowska D, Piekarska K, Sakowska J, Studziński M, Tymoniuk B, Adamski P, Jassem-Bobowicz J, Wydra P, Leszczyńska K, Świątkowska-Stodulska R, Kwiatkowski S, Preis K, Trzonkowski P, Marek-Trzonkowska N, Zieliński M. KIR- ligand interactions in hypertensive disorders in pregnancy. Front Immunol. 2022;15(13): 868175. https://doi.org/10.3389/fimmu.2022.868175.

    Article  Google Scholar 

  67. Yang X, Meng T. Killer-cell immunoglobulin-like receptor/human leukocyte antigen-C combination and ‘great obstetrical syndromes’ (review). Exp Ther Med. 2021;22(4):1178. https://doi.org/10.3892/etm.2021.10612. 

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Walch M, Dotiwala F, Mulik S, Thiery J, Kirchhausen T, Clayberger C, Krensky AM, Martinvalet D, Lieberman J. Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes. Cell. 2014;157(6):1309–23. https://doi.org/10.1016/j.cell.2014.03.062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Iweha C, Graham A, Cui W, Marsh C, Nothnick WB. The uterine natural killer cell, cytotoxic T lymphocyte, and granulysin levels are elevated in the endometrium of women with nonstructural abnormal uterine bleeding. F S Sci. 2022;3(3):246–54. https://doi.org/10.1016/j.xfss.2022.04.003. 

    Article  PubMed  Google Scholar 

  70. De Martinis M, Ginaldi L, Sirufo MM, Pioggia G, Calapai G, Gangemi S, Mannucci C. Alarmins in osteoporosis, RAGE, IL-1, and IL-33 pathways: a literature review. Medicina (Kaunas). 2020;56(3):138. https://doi.org/10.3390/medicina56030138.

    Article  PubMed  Google Scholar 

  71. Crespo ÂC, Mulik S, Dotiwala F, Ansara JA, Sen Santara S, Ingersoll K, Ovies C, Junqueira C, Tilburgs T, Strominger JL, Lieberman J. Decidual NK cells transfer granulysin to selectively kill bacteria in trophoblasts. Cell. 2020;182(5):1125-1139.e18. https://doi.org/10.1016/j.cell.2020.07.019. 

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bouwman AC, van Daalen KR, Crnko S, Ten Broeke T, Bovenschen N. Intracellular and extracellular roles of granzyme K. Front Immunol. 2021;4(12): 677707. https://doi.org/10.3389/fimmu.2021.677707.

    Article  Google Scholar 

  73. de Jong LC, Crnko S, Ten Broeke T, Bovenschen N. Noncytotoxic functions of killer cell granzymes in viral infections. PLoS Pathog. 2021;17(9): e1009818. https://doi.org/10.1371/journal.ppat.1009818.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Gross C, Koelch W, DeMaio A, Arispe N, Multhoff G. Cell surface-bound heat shock protein 70 (Hsp70) mediates perforin-independent apoptosis by specific binding and uptake of granzyme B. J Biol Chem. 2003;278(42):41173–81. https://doi.org/10.1074/jbc.M302644200.

    Article  CAS  PubMed  Google Scholar 

  75. Krzewski K, Coligan JE. Human NK cell lytic granules and regulation of their exocytosis. Front Immunol. 2012;9(3):335. https://doi.org/10.3389/fimmu.2012.00335.

    Article  Google Scholar 

  76. Hirst CE, Buzza MS, Sutton VR, Trapani JA, Loveland KL, Bird PI. Perforin-independent expression of granzyme B and proteinase inhibitor 9 in human testis and placenta suggests a role for granzyme B-mediated proteolysis in reproduction. Mol Hum Reprod. 2001;7(12):1133–42. https://doi.org/10.1093/molehr/7.12.1133. 

    Article  CAS  PubMed  Google Scholar 

  77. El-Badawy O, Abbas AM, Radwan E, Makboul R, Khamis AA, Ali M, Elkabsh MM, Bakr MH, Zahran AM. Cross-talk between mucosal-associated invariant T, natural killer, and natural killer T cell populations is implicated in the pathogenesis of placenta accreta spectrum. Inflammation. 2023;46(4):1192–208. https://doi.org/10.1007/s10753-023-01799-1. 

    Article  CAS  PubMed  Google Scholar 

  78. Prager I, Watzl C. Mechanisms of natural killer cell-mediated cellular cytotoxicity. J Leukoc Biol. 2019;105(6):1319–29. https://doi.org/10.1002/JLB.MR0718-269R. 

    Article  CAS  PubMed  Google Scholar 

  79. Piedra-Quintero ZL, Wilson Z, Nava P, Guerau-de-Arellano M. CD38: an immunomodulatory molecule in inflammation and autoimmunity. Front Immunol. 2020;30(11): 597959. https://doi.org/10.3389/fimmu.2020.597959.

    Article  Google Scholar 

  80. Schuh W, Mielenz D, Jäck HM. Unraveling the mysteries of plasma cells. Adv Immunol. 2020;146:57–107. https://doi.org/10.1016/bs.ai.2020.01.002. 

    Article  CAS  PubMed  Google Scholar 

  81. Le Gars M, Seiler C, Kay AW, Bayless NL, Starosvetsky E, Moore L, Shen-Orr SS, Aziz N, Khatri P, Dekker CL, Swan GE, Davis MM, Holmes S, Blish CA. Pregnancy-induced alterations in NK cell phenotype and function. Front Immunol. 2019;23(10):2469. https://doi.org/10.3389/fimmu.2019.02469.

    Article  Google Scholar 

  82. Le Gars M, Seiler C, Kay AW, Bayless NL, Sola E, Starosvetsky E, Moore L, Shen-Orr SS, Aziz N, Khatri P, Dekker CL, Swan GE, Davis MM, Holmes S, Blish CA. CD38 contributes to human natural killer cell responses through a role in immune synapse formation. BioRxiv 2019: 349084. https://doi.org/10.1101/349084

  83. Perrone R, Kumaar PVA, Haky L, Hahn C, Riley R, Balough J, Zaza G, Soygur B, Hung K, Prado L, Kasler HG, Tiwari R, Matsui H, Hormazabal GV, Duncan FE, Verdin E. CD38 regulates ovarian function and fecundity via NAD+ metabolism. bioRxiv 2023 05.08.539779. https://doi.org/10.1101/2023.05.08.539779

  84. Cohnen A, Chiang SC, Stojanovic A, Schmidt H, Claus M, Saftig P, Janßen O, Cerwenka A, Bryceson YT, Watzl C. Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage. Blood. 2013;122(8):1411–8. https://doi.org/10.1182/blood-2012-07-441832. 

    Article  CAS  PubMed  Google Scholar 

  85. Alter G, Malenfant JM, Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods. 2004;294(1–2):15–22. https://doi.org/10.1016/j.jim.2004.08.008.

    Article  CAS  PubMed  Google Scholar 

  86. Miko E, Manfai Z, Meggyes M, Barakonyi A, Wilhelm F, Varnagy A, Bodis J, Illes Z, Szekeres-Bartho J, Szereday L. Possible role of natural killer and natural killer T-like cells in implantation failure after IVF. Reprod Biomed Online. 2010;21(6):750–6. https://doi.org/10.1016/j.rbmo.2010.07.012. 

    Article  PubMed  Google Scholar 

  87. Yan N, Lee P, Jie H, Yuan Y, Zhou C. The associations of natural killer cell functions during the embryo implantation window with pregnancy outcomes in women for whom the number of peripheral blood natural killer cells cannot be applied as a therapeutic index for immunological abnormalities in unexplained recurrent pregnancy loss. Research Square. 2023. https://doi.org/10.21203/rs.3.rs-3000344/v1.

  88. Cifaldi L, Melaiu O, Giovannoni R, Benvenuto M, Focaccetti C, Nardozi D, Barillari G, Bei R. DNAM-1 chimeric receptor-engineered NK cells: a new frontier for CAR-NK cell-based immunotherapy. Front Immunol. 2023;8(14):1197053. https://doi.org/10.3389/fimmu.2023.1197053.

    Article  Google Scholar 

  89. Cifaldi L, Doria M, Cotugno N, Zicari S, Cancrini C, Palma P, Rossi P. DNAM-1 activating receptor and its ligands: how do viruses affect the NK cell-mediated immune surveillance during the various phases of infection? Int J Mol Sci. 2019;20(15):3715. https://doi.org/10.3390/ijms20153715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zingoni A, Ardolino M, Santoni A, Cerboni C. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. Front Immunol. 2013;9(3):408. https://doi.org/10.3389/fimmu.2012.00408.

    Article  Google Scholar 

  91. Ge Z, Peppelenbosch MP, Sprengers D, Kwekkeboom J. TIGIT, the next step towards successful combination immune checkpoint therapy in cancer. Front Immunol. 2021;22(12): 699895. https://doi.org/10.3389/fimmu.2021.699895.

    Article  Google Scholar 

  92. Wang Y, Li D, Yu T, Hu M, Xing J, Bai S, Qu W, Tong X. Dynamics of TIGIT and PD-1 expression on NK cells during the course of normal pregnancy. Immunol Lett. 2021;230:42–8. https://doi.org/10.1016/j.imlet.2020.12.005. 

    Article  CAS  PubMed  Google Scholar 

  93. Meggyes M, Nagy DU, Feik T, Boros A, Polgar B, Szereday L. Examination of the TIGIT-CD226-CD112-CD155 immune checkpoint network during a healthy pregnancy. Int J Mol Sci. 2022;23(18):10776. https://doi.org/10.3390/ijms231810776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Meggyes M, Nagy DU, Saad Al Deen I, Parkanyi B, Szereday L. CD8+ and CD8- NKT cells exhibit phenotypic changes during pregnancy. Immunol Invest. 2023;52(1):35–51. https://doi.org/10.1080/08820139.2022.2119863. 

    Article  CAS  PubMed  Google Scholar 

  95. Szereday L, Nagy DU, Csiszar B, Kevey D, Feik T, Meggyes M. Examination of the TIGIT, CD226, CD112, and CD155 immune checkpoint molecules in peripheral blood mononuclear cells in women diagnosed with early-onset preeclampsia. Biomedicines. 2021;9(11):1608. https://doi.org/10.3390/biomedicines9111608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kamrani A, Soltani-Zangbar MS, Shiri S, Yousefzadeh Y, Pourakbari R, Aghebati-Maleki L, Mehdizadeh A, Danaii S, Jadidi-Niaragh F, Yousefi B, Kafil HS, Hojjat-Farsangi M, Motavalli R, Zolfaghari M, Haji-Fatahaliha M, Mahmoodpoor A, Ahmadian Heris J, Emdadi A, Yousefi M. TIGIT and CD155 as immune-modulator receptor and ligand on CD4+ T cells in preeclampsia patients. Immunol Invest. 2022;51(4):1023–38. https://doi.org/10.1080/08820139.2021.1904976. 

    Article  CAS  PubMed  Google Scholar 

  97. Habets DHJ, Schlütter A, van Kuijk SMJ, Spaanderman MEA, Al-Nasiry S, Wieten L. Natural killer cell profiles in recurrent pregnancy loss: Increased expression and positive associations with TACTILE and LILRB1. Am J Reprod Immunol. 2022;88(5):e13612. https://doi.org/10.1111/aji.13612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer. 2020;8(1): e000911. https://doi.org/10.1136/jitc-2020-000911.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Li YH, Zhou WH, Tao Y, Wang SC, Jiang YL, Zhang D, Piao HL, Fu Q, Li DJ, Du MR. 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. 2016;13(1):73–81. https://doi.org/10.1038/cmi.2014.126. 

    Article  CAS  PubMed  Google Scholar 

  100. Cui L, Sun F, Xu Y, Li M, Chen L, Chen C, Qian J, Li D, Du M, Wang S. Tim-3 coordinates macrophage-trophoblast crosstalk via angiogenic growth factors to promote pregnancy maintenance. Int J Mol Sci. 2023;24(2):1538. https://doi.org/10.3390/ijms24021538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Qi H, Li Y, Liu X, Jiang Y, Li Z, Xu X, Zhang H, Hu X. Tim-3 regulates the immunosuppressive function of decidual MDSCs via the Fyn-STAT3-C/EBPβ pathway during Toxoplasma gondii infection. PLoS Pathog. 2023;19(4): e1011329. https://doi.org/10.1371/journal.ppat.1011329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhu W, Tan YQ, Wang FY. Tim-3: an inhibitory immune checkpoint is associated with maternal-fetal tolerance and recurrent spontaneous abortion. Clin Immunol. 2022;245: 109185. https://doi.org/10.1016/j.clim.2022.109185. 

    Article  CAS  PubMed  Google Scholar 

  103. Li Y, Zhang J, Zhang D, Hong X, Tao Y, Wang S, Xu Y, Piao H, Yin W, Yu M, Zhang Y, Fu Q, Li D, Chang X, Du M. Tim-3 signaling in peripheral NK cells promotes maternal-fetal immune tolerance and alleviates pregnancy loss. Sci Signal. 2017;10(498):4323. https://doi.org/10.1126/scisignal.aah4323. 

    Article  CAS  Google Scholar 

  104. Lu C, Chen H, Wang C, Yang F, Li J, Liu H, Chen G. An emerging role of TIM3 expression on t cells in chronic kidney inflammation. Front Immunol. 2022;26(12): 798683. https://doi.org/10.3389/fimmu.2021.798683.PMID:35154075;PMCID:PMC8825483.

    Article  Google Scholar 

  105. Chen Z, Huang J, Kwak-Kim J, Wang W. Immune checkpoint inhibitors and reproductive failures. J Reprod Immunol. 2023;156: 103799. https://doi.org/10.1016/j.jri.2023.103799.

    Article  CAS  PubMed  Google Scholar 

  106. Woon EV, Nikolaou D, MacLaran K, Norman-Taylor J, Bhagwat P, Cuff AO, Johnson MR, Male V. Uterine NK cells underexpress KIR2DL1/S1 and LILRB1 in reproductive failure. Front Immunol. 2023;13(13):1108163. https://doi.org/10.3389/fimmu.2022.1108163.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Li M, Sun F, Qian J, Chen L, Li D, Wang S, Du M. Tim-3/CTLA-4 pathways regulate decidual immune cells-extravillous trophoblasts interaction by IL-4 and IL-10. FASEB J. 2021;35(8): e21754. https://doi.org/10.1096/fj.202100142R. 

    Article  CAS  PubMed  Google Scholar 

  108. Zych M, Roszczyk A, Kniotek M, Dąbrowski F, Zagożdżon R. Differences in immune checkpoints expression (TIM-3 and PD-1) on T cells in women with recurrent miscarriages-preliminary studies. J Clin Med. 2021;10(18):4182. https://doi.org/10.3390/jcm10184182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Marron K, Harrity C. Correlation of peripheral blood and endometrial immunophenotyping in ART: is peripheral blood sampling useful? J Assist Reprod Genet. 2023;40(2):381–7. https://doi.org/10.1007/s10815-022-02696-6. 

    Article  PubMed  Google Scholar 

  110. Lash GE, Bulmer JN, Li TC, Innes BA, Mariee N, Patel G, Sanderson J, Quenby S, Laird SM. Standardisation of uterine natural killer (uNK) cell measurements in the endometrium of women with recurrent reproductive failure. J Reprod Immunol. 2016;116:50–9. https://doi.org/10.1016/j.jri.2016.04.290. 

    Article  CAS  PubMed  Google Scholar 

  111. Lédée N, Petitbarat M, Prat-Ellenberg L, Dray G, Cassuto GN, Chevrier L, Kazhalawi A, Vezmar K, Chaouat G. Endometrial immune profiling: a method to design personalized care in assisted reproductive medicine. Front Immunol. 2020;4(11):1032. https://doi.org/10.3389/fimmu.2020.01032.

    Article  Google Scholar 

  112. Lédée N, Prat-Ellenberg L, Chevrier L, Balet R, Simon C, Lenoble C, Irani EE, Bouret D, Cassuto G, Vitoux D, Vezmar K, Bensussan A, Chaouat G, Petitbarat M. Uterine immune profiling for increasing live birth rate: a one-to-one matched cohort study. J Reprod Immunol. 2017;119:23–30. https://doi.org/10.1016/j.jri.2016.11.007. 

    Article  PubMed  Google Scholar 

  113. Chernyshov VP, Dons’koi BV, Sudoma IO, Goncharova YO. Favorable immune phenotype predicts successful implantation and pregnancy. Immunol Lett. 2014;162(2):217–21. https://doi.org/10.1016/j.imlet.2014.10.022.

    Article  CAS  PubMed  Google Scholar 

  114. Fan X, Yang Y, Wen Q, Li Y, Meng F, Liao J, Chen H, Lu GX, Lin G, Gong F. CD19 and intraglandular CD163-positivity as prognostic indicators of pregnancy outcome in CD138-negative women with a previous fresh-embryo-transfer failure. J Reprod Immunol. 2021;147: 103362. https://doi.org/10.1016/j.jri.2021.103362. 

    Article  CAS  PubMed  Google Scholar 

  115. Dons’koi BV, Osypchuk DV, Chernyshov VP, Khazhylenko KG. Expression of natural cytotoxicity receptor NKp46 on peripheral blood natural killer cells in women with a history of recurrent implantation failures. J Obstet Gynaecol Res. 2021;47(3):1009–15. https://doi.org/10.1111/jog.14631. 

    Article  CAS  PubMed  Google Scholar 

  116. Hviid Saxtorph M, Persson G, Hallager T, Birch Petersen K, Eriksen JO, Larsen LG, Macklon N, Hviid TVF. Are different markers of endometrial receptivity telling us different things about endometrial function? Am J Reprod Immunol. 2020;84(6):e13323. https://doi.org/10.1111/aji.13323. 

    Article  CAS  PubMed  Google Scholar 

  117. Santillán I, Lozano I, Illán J, Verdú V, Coca S, Bajo-Arenas JM, Martinez F. Where and when should natural killer cells be tested in women with repeated implantation failure? J Reprod Immunol. 2015;108:142–8. https://doi.org/10.1016/j.jri.2014.12.009. 

    Article  CAS  PubMed  Google Scholar 

  118. Salazar MD, Wang WJ, Skariah A, He Q, Field K, Nixon M, Reed R, Dambaeva S, Beaman K, Gilman-Sachs A, Kwak-Kim J. Post-hoc evaluation of peripheral blood natural killer cell cytotoxicity in predicting the risk of recurrent pregnancy losses and repeated implantation failures. J Reprod Immunol. 2022;150:103487. https://doi.org/10.1016/j.jri.2022.103487.

    Article  CAS  PubMed  Google Scholar 

  119. Fan X, Zhao Q, Li Y, Chen Z, Liao J, Chen H, Meng F, Lu GX, Lin G, Gong F. Immune profiling and RNA-seq uncover the cause of partial unexplained recurrent implantation failure. Int Immunopharmacol. 2023;121: 110513. https://doi.org/10.1016/j.intimp.2023.110513. 

    Article  CAS  PubMed  Google Scholar 

  120. Ganeva R, Parvanov D, Vidolova N, Ruseva M, Handzhiyska M, Arsov K, Decheva I, Metodiev D, Moskova-Doumanova V, Stamenov G. Endometrial immune cell ratios and implantation success in patients with recurrent implantation failure. J Reprod Immunol. 2023;156: 103816. https://doi.org/10.1016/j.jri.2023.103816. 

    Article  CAS  PubMed  Google Scholar 

  121. Oikonomou G, Vlachadis N, Tsamadias V, Lambrinoudaki I, Deligeoroglou E, Vlahos NF, Economou E. Human leukocyte antigen alleles compatibility and immunophenotypic profile associations in infertile couples. Cureus. 2023;15(3): e36584. https://doi.org/10.7759/cureus.36584.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Dons Koi BV, Osypchuk DV, Baksheev SM, Sudoma IO, Goncharova YO, Palyha IE, Sirenko VY, Khazhylenko KG, Onyshchuk O, Anoshko Y, Shapovalenko NO. A blinded multicenter investigation: accentuated NK lymphocyte CD335 (NKp46) expression predicts reproductive failures after IVF. Immunol Lett. 2022;251–252:47–55. https://doi.org/10.1016/j.imlet.2022.10.003. 

    Article  CAS  PubMed  Google Scholar 

  123. Chen X, Diao L, Lian R, Qi L, Yu S, Liu S, Lin S, Xue Z, Zeng Y. Potential impact of maternal vitamin D status on peripheral blood and endometrium cellular immunity in women with recurrent implantation failure. Am J Reprod Immunol. 2020;84(1):e13243. https://doi.org/10.1111/aji.13243. 

    Article  CAS  PubMed  Google Scholar 

  124. Kuon RJ, Weber M, Heger J, Santillán I, Vomstein K, Bär C, Strowitzki T, Markert UR, Toth B. Uterine natural killer cells in patients with idiopathic recurrent miscarriage. Am J Reprod Immunol. 2017;78(4). https://doi.org/10.1111/aji.12721. 

  125. Zhang Y, Huang C, Lian R, Xu J, Fu Y, Zeng Y, Tu W. The low cytotoxic activity of peripheral blood NK cells may relate to unexplained recurrent miscarriage. Am J Reprod Immunol. 2021;85(6):e13388. https://doi.org/10.1111/aji.13388.

    Article  CAS  PubMed  Google Scholar 

  126. Diao L, Cai S, Huang C, Li L, Yu S, Wang L, Liu S, Li Y, Zeng Y. New endometrial immune cell-based score (EI-score) for the prediction of implantation success for patients undergoing IVF/ICSI. Placenta. 2020;15(99):180–8. https://doi.org/10.1016/j.placenta.2020.07.025. 

    Article  CAS  Google Scholar 

  127. Tuckerman E, Mariee N, Prakash A, Li TC, Laird S. Uterine natural killer cells in peri-implantation endometrium from women with repeated implantation failure after IVF. J Reprod Immunol. 2010;87(1–2):60–6. https://doi.org/10.1016/j.jri.2010.07.001. 

    Article  CAS  PubMed  Google Scholar 

  128. Chen X, Mariee N, Jiang L, Liu Y, Wang CC, Li TC, Laird S. Measurement of uterine natural killer cell percentage in the periimplantation endometrium from fertile women and women with recurrent reproductive failure: establishment of a reference range. Am J Obstet Gynecol. 2017;217(6):680.e1-680.e6. https://doi.org/10.1016/j.ajog.2017.09.010. 

    Article  PubMed  Google Scholar 

  129. Jiang R, Yan G, Xing J, Wang Z, Liu Y, Wu H, Fan X, Zhou J, Ding L, Sun H. Abnormal ratio of CD57+ cells to CD56+ cells in women with recurrent implantation failure. Am J Reprod Immunol. 2017;78(5). https://doi.org/10.1111/aji.12708. 

  130. Mai C, Fukui A, Takeyama R, Yamamoto M, Saeki S, Yamaya A, Kato T, Ukita Y, Wakimoto Y, Shibahara H. NK cells that differ in expression of NKp46 might play different roles in endometrium. J Reprod Immunol. 2021;147: 103367. https://doi.org/10.1016/j.jri.2021.103367. 

    Article  CAS  PubMed  Google Scholar 

  131. Male V. Medawar and the immunological paradox of pregnancy: in context. Oxf Open Immunol. 2020;2(1):006. https://doi.org/10.1093/oxfimm/iqaa006. 

    Article  Google Scholar 

  132. Sacks G. Enough! Stop the arguments and get on with the science of natural killer cell testing. Hum Reprod. 2015;30(7):1526–31. https://doi.org/10.1093/humrep/dev096. 

    Article  CAS  PubMed  Google Scholar 

  133. Oh S, Chun S, Hwang S, Kim J, Cho Y, Lee J, Kwack K, Choi SW. Vitamin D and exercise are major determinants of natural killer cell activity, which is age- and gender-specific. Front Immunol. 2021;23(12): 594356. https://doi.org/10.3389/fimmu.2021.594356.

    Article  CAS  Google Scholar 

  134. Robertson SA, Moldenhauer LM, Green ES, Care AS, Hull ML. Immune determinants of endometrial receptivity: a biological perspective. Fertil Steril. 2022;117(6):1107–20. https://doi.org/10.1016/j.fertnstert.2022.04.023. 

    Article  CAS  PubMed  Google Scholar 

  135. Berbic M, Fraser IS. Immunology of normal and abnormal menstruation. Womens Health (Lond). 2013;9(4):387–95. https://doi.org/10.2217/whe.13.32. 

    Article  CAS  PubMed  Google Scholar 

  136. Capellino S, Claus M, Watzl C. Regulation of natural killer cell activity by glucocorticoids, serotonin, dopamine, and epinephrine. Cell Mol Immunol. 2020;17(7):705–11. https://doi.org/10.1038/s41423-020-0477-9. 

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Brioso KE, Cristina FS, Costa L, Ouakinin S. Correlation between emotional regulation and peripheral lymphocyte counts in colorectal cancer patients. PeerJ. 2020;14(8): e9475. https://doi.org/10.7717/peerj.9475.

    Article  Google Scholar 

  138. Millard AL, Valli PV, Stussi G, Mueller NJ, Yung GP, Seebach JD. Brief exercise increases peripheral blood NK cell counts without immediate functional changes, but impairs their responses to ex vivo stimulation. Front Immunol. 2013;29(4):125. https://doi.org/10.3389/fimmu.2013.00125.

    Article  CAS  Google Scholar 

  139. Hicks KM, Orange ST, Dulson D, Ansdell P, Todryk S, Gilbert S, Saxton JM. The effect of menstrual-cycle phase on immune responses to a 5-km cycling time trial: an exploratory study. Int J Sports Physiol Perform. 2023;18(4):435–9. https://doi.org/10.1123/ijspp.2022-0130. 

    Article  PubMed  Google Scholar 

  140. Gustafson MP, DiCostanzo AC, Wheatley CM, Kim CH, Bornschlegl S, Gastineau DA, Johnson BD, Dietz AB. A systems biology approach to investigating the influence of exercise and fitness on the composition of leukocytes in peripheral blood. J Immunother Cancer. 2017;18(5):30. https://doi.org/10.1186/s40425-017-0231-8.

    Article  Google Scholar 

  141. Fan X, Li X, Li Y, Liao J, Chen H, Li Y, Lu GX, Lin G, Gong F. Endometrial CD138 count appears to be a negative prognostic indicator for patients who have experienced previous embryo transfer failure. Fertil Steril. 2019;112(6):1103–11. https://doi.org/10.1016/j.fertnstert.2019.08.006. 

    Article  CAS  PubMed  Google Scholar 

  142. Easthope E. Flow cytometry sample-prep mistakes to avoid. Biocompare. 2019. Retrieved February 8, 2023. https://www.biocompare.com/Editorial-Articles/357846-Flow-Cytometry-Sample-Prep-Mistakes-to-Avoid/. Accessed 27 Feb 2023

  143. Diks AM, Bonroy C, Teodosio C, Groenland RJ, de Mooij B, de Maertelaere E, Neirynck J, Philippé J, Orfao A, van Dongen JJM, Berkowska MA. Impact of blood storage and sample handling on quality of high dimensional flow cytometric data in multicenter clinical research. J Immunol Methods. 2019;475: 112616. https://doi.org/10.1016/j.jim.2019.06.007.

    Article  CAS  PubMed  Google Scholar 

  144. Kim SW, Roh J, Park CS. Immunohistochemistry for pathologists: protocols, pitfalls, and tips. J Pathol Transl Med. 2016;50(6):411–8. https://doi.org/10.4132/jptm.2016.08.08.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Dons’koi B, Onyshchuk O, Kononenko I, Sirenko V, Bodnar N, Serbyn A, Kozachok A, Brovarska Y, Osypchuk D, Anochko Y, Chernychov V. Accentuated peripheral blood NK cytotoxicity forms an unfavorable background for embryo implantation and gestation. Diagnostics (Basel). 2022;12(4):908. https://doi.org/10.3390/diagnostics12040908.

    Article  PubMed  Google Scholar 

  146. Karami N, Boroujerdnia MG, Nikbakht R, Khodadadi A. Enhancement of peripheral blood CD56(dim) cell and NK cell cytotoxicity in women with recurrent spontaneous abortion or in vitro fertilization failure. J Reprod Immunol. 2012;95(1–2):87–92. https://doi.org/10.1016/j.jri.2012.06.005.

    Article  CAS  PubMed  Google Scholar 

  147. Chernyshov VP, Sudoma IO, Dons’koi BV, Kostyuchyk AA, Masliy YV. Elevated NK cell cytotoxicity, CD158a expression in NK cells and activated T lymphocytes in peripheral blood of women with IVF failures. Am J Reprod Immunol. 2010;64(1):58–67. https://doi.org/10.1111/j.1600-0897.2010.00825.x.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Author information

Authors and Affiliations

  1. Faculdade de Medicina, Pontifícia Universidade Católica de Campinas, Av. John Boyd Dunlop S/N - Jardim Ipaussurama, Campinas, São Paulo, 13034-685, Brazil

    Juliana Peron Gothe & Amílcar Castro de Mattos

  2. Faculdade de Biomedicina, Pontifícia Universidade Católica de Campinas, Campinas, São Paulo, Brazil

    Carolina Fernanda Silveira

  3. Faculdades Integradas Einstein de Limeira, Limeira, São Paulo, Brazil

    Kelly Cristina Malavazi

Authors
  1. Juliana Peron Gothe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amílcar Castro de Mattos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carolina Fernanda Silveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kelly Cristina Malavazi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors were responsible for conceiving and designing the analysis.

J. P. G. collected the data, performed the analysis, and wrote this paper.

All authors agreed on this final version of the paper.

Corresponding author

Correspondence to Juliana Peron Gothe.

Ethics declarations

Ethical Approval

This is a narrative literature review and did not involve live humans or other animals.

Unfortunately, the system required this file in order to submit this review article.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gothe, J.P., de Mattos, A.C., Silveira, C.F. et al. Exploring Natural Killer Cell Testing in Embryo Implantation and Reproductive Failure: An Overview of Techniques and Controversies. Reprod. Sci. 31, 603–632 (2024). https://doi.org/10.1007/s43032-023-01372-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-023-01372-z

Keywords

Search

Navigation