The role of peripheral and endometrial natural killer cells in recurrent reproductive losses

Zagainova V.A., Kogan I.Yu., Bespalova O.N., Selkov S.A., Sokolov D.I.

D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductology, Saint Petersburg, Russia
Many infertile couples cannot achieve pregnancy after repeatedly implemented assisted reproductive technology (ART) programs, as well as its successful prolongation, even with the transfer of good-quality euploid embryos. In this connection, repeated implantation failures (RIFs) in the in vitro fertilization (IVF) protocols and recurrent miscarriage (RM) are important medical and social problems. The generally accepted methods
of examination do not explain the cause of repeated reproductive failures in 30-50% of cases. Among the causes
of idiopathic reproductive losses, the immunological factor, including both systemic and local changes in the immune status, plays a leading role. Innate immune cells have been established to play a central role in the processes of implantation, placentation, formation, and maintenance of immune tolerance towards a developing embryo. Of great scientific and practical interest are natural killer (NK) cells that are the largest population of endometrial lymphocytes, changes in the quantitative and qualitative profile of which in both peripheral blood and the endometrium are associated with conditions, such as RIF, RM, uterine fibroids, endometriosis, preeclampsia and others.
Conclusion. The conducted studies indicate the important role of both subpopulations of NK cells in a woman’s reproductive health. However, to date, there are insufficient data on the function and mechanisms of action of NK cells in reproductive losses, which requires further investigation.


NK cells
natural killers
IVF failures
repeated implantation failures
recurrent miscarriage


  1. Seillet C., Belz G.T., Huntington N.D. Development, homeostasis, and heterogeneity of NK Cells and ILC1. Curr. Top. Microbiol. Immunol. 2016; 395: 37-61.
  2. Zhou J., Tian Z., Peng H. Tissue-resident NK cells and other innate lymphoid cells. Adv. Immunol. 2020; 145: 37-53.
  3. Geiger T.L., Sun J.C. Development and maturation of natural killer cells. Curr. Opin. Immunol. 2016; 39: 82-9.
  4. Абакушина Е.В., Кузьмина Е.Г., Коваленко Е.И. Основные свойства и функции NK-клеток человека. Иммунология. 2012; 33(4): 220-4. [Abakushina E.V., Kuzmina E.G., Kovalenko E.I. The main characteristics of human natural killer cells. Immunology. 2012; 33(4): 220-4. (in Russian)].
  5. Михайлова В.А., Овчинникова О.М., Онохина Я.С., Чугунова А.А., Зайнулина М.С., Сельков С.А., Соколов Д.И. Функциональная активность NK-клеток периферической крови при гестозе. Иммунология. 2014; 35(1): 4-8. [Mikhaylova V.A., Ovchinnikova O.M., Onohina Y.S., Chugunova A.A., Zainulina M.S., Selkov S.A., Sokolov D.I. Functional activity of peripheral blood NK-cells at preeclampsia. Immunology. 2014; 35(1): 4-8. (in Russian)].
  6. Lam V.C., Lanier L.L. NK cells in host responses to viral infections. Curr. Opin. Immunol. 2017; 44: 43-51.
  7. Angelo L.S., Banerjee P.P., Monaco-Shawver L., Rosen J.B., Makedonas G., Forbes L.R. et al. Practical NK cell phenotyping and variability in healthy adults. Immunol. Res. 2015; 62(3): 341-56.
  8. Hudspeth K., Donadon M., Cimino M., Pontarini E., Tentorio P., Preti M. et al. Human liver-resident CD56bright/CD16neg NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways. J. Autoimmun. 2016; 66: 40-50.
  9. Marcenaro E., Carlomagno S., Pesce S., Della Chiesa M., Parolini S., Moretta A., Sivori S. NK cells and their receptors during viral infections. Immunotherapy. 2011; 3(9): 1075-86.
  10. Михайлова В.А., Белякова К.Л., Сельков С.А., Соколов Д.И. Особенности дифференцировки NK-клеток: CD56dim и CD56bright NK-клетки во время и вне беременности. Медицинская иммунология. 2017; 19(1): 19-26. [Mikhailova V.A., Belyakova K.L., Selkov S.A., Sokolov D.I. Peculiarities of NK cells differentiation: CD56dim and CD56bright NK cells at pregnancy and in non-pregnant state. Medical Immunology (Russia). 2017; 19(1): 19-26. (in Russin)].
  11. Lee S., Kim J., Jang B., Hur S., Jung U., Kil K. et al. Fluctuation of peripheral blood T, B, and NK cells during a menstrual cycle of normal healthy women. J. Immunol. 2010; 185(1): 756-62.
  12. Souza S., Castro F., Mendonça H., Palma P.V., Morais F.R., Ferriani R.A., Voltarelli J.C. Influence of menstrual cycle on NK activity. J. Reprod. Immunol. 2001; 50(2): 151-9.
  13. Gregory C., Lee H., Scott I., Golding P. Phenotypic heterogeneity and recycling capacity of natural killer cells in normal human pregnancy. J. Reprod. Immunol. 1987; 11(2): 135-45.
  14. Yovel G., Shakhar K., Ben-Eliyahu S. The effects of sex, menstrual cycle, and oral contraceptives on the number and activity of natural killer cells. Gynecol. Oncol. 2001; 81(2): 254-62.
  15. Northern A.L.D., Rutter S.M., Peterson C.M. Cyclic changes in the concentrations of peripheral blood immune cells during the normal menstrual cycle. Exp. Biol. Med. 1994; 207(1): 81-8. 10.3181/00379727-207-43795.
  16. Fu B., Wei H. Decidual natural killer cells and the immune microenvironment at the maternal-fetal interface. Sci. China Life Sci. 2016; 59(12): 1224-31.
  17. Sojka D.K., Yang L., Plougastel-Douglas B., Higuchi D.A., Croy B.A., Yokoyama W.M. Cutting edge: local proliferation of uterine tissue-resident NK cells during decidualization in mice. J. Immunol. 2018; 201(9): 2551-6.
  18. Lockwood C.J., Huang S.J., Chen C.P., Huang Y., Xu J., Faramarzi S. et al. Decidual cell regulation of natural killer cell–recruiting chemokines. Am. J. Pathol. 2013; 183(3): 841-56.
  19. Cerdeira A.S., Rajakumar A., Royle C.M., Lo A., Husain Z., Thadhani R.I. et al. 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.
  20. Chazara O., Xiong S., Moffett A. Maternal KIR and fetal HLA-C: a fine balance. J. Leukoc. Biol. 2011; 90(4): 703-16.
  21. Apps R., Sharkey A., Gardner L., Male V., Kennedy P., Masters L. et al. Ex vivo functional responses to HLA-G differ between blood and decidual NK cells. Mol. Hum. Reprod. 2011; 17(9): 577-86.
  22. Coupel S., Moreau A., Hamidou M., Horejsi V., Soulillou J.P., Charreau B. Expression and release of soluble HLA-E is an immunoregulatory feature of endothelial cell activation. Blood. 2007; 109(7): 2806-14.
  23. Jabrane-Ferrat N. Features of human decidual NK cells in healthy pregnancy and during viral infection. Front. Immunol. 2019; 10: 1397.
  24. Sojka D.K., Yang L., Yokoyama W.M. Uterine natural killer cells: To protect and to nurture. Birth Defects Res. 2018; 110(20): 1531-8.
  25. Gong H., Chen Y., Xu J., Xie X., Yu D., Yang B., Kuang H. The regulation of ovary and conceptus on the uterine natural killer cells during early pregnancy. Reprod. Biol. Endocrinol. 2017; 15(1): 73.
  26. Mekinian A., Cohen J., Alijotas-Reig J., Carbillon L.., Nicaise-Roland P., Kayem G. et al. Unexplained recurrent miscarriage and recurrent implantation failure: is there a place for immunomodulation? Am. J. Reprod. Immunol. 2016; 76(1): 8-28.
  27. Marron K., Walsh D., Harrity C. Detailed endometrial immune assessment of both normal and adverse reproductive outcome populations. J. Assist. Reprod. Genet. 2018; 36(2): 199-210.
  28. Tuckerman E., Mariee N., Prakash A., Li T.C., 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.
  29. Chen X., Mariee N., Jiang L., Liu Y., Wang C.C., Li T.C., 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.
  30. Sacks G., Yang Y., Smith S., Chapman M. Detailed analysis of peripheral blood natural killer cells in women with repeated IVF failure. J. Reprod. Immunol. 2012; 94(1): 24.
  31. Santillán I., Lozano I., Illán J., Verdú V., Coca S., Bajo-Arenas J.M., Martinez F. Where and when should natural killer cells be tested in women with repeated implantation failure? J. Reprod. Immunol. 2015; 108: 142-8.
  32. Ho Y.K., Chen H.H., Huang C.C., Lee C.I., Lin P.Y., Lee M.S., Lee T.H. Peripheral CD56 CD16 NK cell populations in the early follicular phase are associated with successful clinical outcomes of intravenous immunoglobulin treatment in women with repeated implantation failure. Front. Endocrinol. (Lausanne). 2020 Jan 21; 10:937.
  33. Zhang H., Huang C., Chen X., Li L., Liu S., Li Y. et al. The number and cytotoxicity and the expression of cytotoxicity-related molecules in peripheral natural killer (NK) cells do not predict the repeated implantation failure (RIF) for the in vitro fertilization patients. Genes Dis. 2020; 7(2): 283-9.
  34. Kolanska K., Suner L., Cohen J., Ben Kraiem Y., Placais L., Fain O. et al. 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.
  35. Seshadri S., Sunkara S.K. Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis. Hum. Reprod. Update. 2014; 20(3): 429-38.
  36. Woon E.V., Day A., Bracewell-Milnes T., Male V., Johnson M. Immunotherapy to improve pregnancy outcome in women with abnormal natural killer cell levels/activity and recurrent miscarriage or implantation failure: A systematic review and meta-analysis. J. Reprod. Immunol. 2020; 142: 103189.
  37. Fukui A., Kwak-Kim J., Ntrivalas E., Gilman-Sachs A., Lee S.-K., Beaman K. Intracellular cytokine expression of peripheral blood natural killer cell subsets in women with recurrent spontaneous abortions and implantation failures. Fertil. Steril. 2008; 89(1): 157-65.
  38. Saito S., Nakashima A., Shima T., Ito M. Th1/Th2/Th17 and regulatory T-Cell paradigm in pregnancy. Am. J. Reprod. Immunol. 2010; 63(6): 601-10.
  39. Соколов Д.И., Сельков С.А. Децидуальные макрофаги: роль в иммунологическом диалоге матери и плода. Иммунология. 2014; 35(2): 113-7. [Sokolov D.I., Selkov S.A. Decidual macrophages: the role in immunologic dialogue of mother and the fetus. Immunology. 2014; 35(2): 113-7. (in Russian)].
  40. Mikhailova V.A., Kudryavtsev I.V., Serebryakova M.K., Milyutina Y.P., Demidova E.S., Panina A.N., Bazhenov D.O., Belikova M.E., Selkov S.A., Sokolov D.I. Trophoblast cell influence on peripheral blood natural killer cell proliferation and phenotype in non-pregnant women and women in early pregnancy. Immunobiology. 2020; 225(3): 151910.
  41. Quenby S., Nik H., Innes B., Lash G., Turner M., Drury J., Bulmer J. Uterine natural killer cells and angiogenesis in recurrent reproductive failure. Hum. Reprod. 2009; 24(1): 45-54.
  42. Azargoon A., Mirrasouli Y., Barough M.S., Barati M., Kokhaei P. The state of peripheral blood natural killer cells and cytotoxicity in women with recurrent pregnancy loss and unexplained infertility. Int. J. Fertil. Steril. 2019; 13(1): 12-7.
  43. Ghafourian M., Karami N., Khodadadi A., Nikbakhat R. Increase of CD69, CD161 and CD94 on NK cells in women with recurrent spontaneous abortion and in vitro fertilization failure. Iran. J. Immunol. 2014; 11(2):84-96.
  44. Baczkowski T., Kurzawa R. Immunophenotypic profiles of peripheral blood lymphocytes on the day of embryo transfer in women undergoing in vitro fertilization. Folia Histochem. Cytobiol. 2007; 45(Suppl. 1): S73-7.
  45. Lissauer D.M., Piper K.P., Moss P.A.H., Kilby M.D. Fetal microchimerism: the cellular and immunological legacy of pregnancy. Expert Rev. Mol. Med. 2009; 11: e33.
  46. Toth B., Vomstein K., Togawa R., Böttcher B., Hudalla H., Strowitzki T., Daniel V., Kuon R.J. The impact of previous live births on peripheral and uterine natural killer cells in patients with recurrent miscarriage. Reprod. Biol. Endocrinol. 2019; 17(1): 72.
  47. Ali S.B., Jeelall Y., Pennell C.E., Hart R., Mclean-Tooke A., Lucas M. The role of immunological testing and intervention in reproductive medicine: A fertile collaboration? Am. J. Reprod. Immunol. 2018; 79(3).
  48. Junovich G., Azpiroz A., Incera E., Ferrer C., Pasqualini A., Gutierrez G. Endometrial CD16 and CD16−NK cell count in fertility and unexplained infertility. Am. J. Reprod. Immunol. 2013; 70(3): 182-9.
  49. Giuliani E., Parkin K.L., Lessey B.A., Young S.L., Fazleabas A.T. Characterization of uterine NK cells in women with infertility or recurrent pregnancy loss and associated endometriosis. Am. J. Reprod. Immunol. 2014; 72(3): 262-9.
  50. Fuchinoue K., Fukui A., Chiba H., Kamoi M., Funamizu A., Taima A. et al. Expression of retinoid-related orphan receptor (ROR)γt on NK22 cells in the peripheral blood and uterine endometrium of women with unexplained recurrent pregnancy loss and unexplained infertility. J. Obstet. Gynaecol. Res. 2016; 42(11): 1541-52.
  51. Kuon R.-J., Weber M., Heger J., Santillán I., Vomstein K., Bär C. et al. Uterine natural killer cells in patients with idiopathic recurrent miscarriage. Am. J. Reprod. Immunol. 2017; 78(4).
  52. Tang A.-W., Alfirevic Z., Turner M.A., Drury J.A., Small R., Quenby S. A feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant. Hum. Reprod. 2013; 28(7): 1743-52.
  53. Ebina Y., Nishino Y., Deguchi M., Maesawa Y., Nakashima Y., Yamada H. Natural killer cell activity in women with recurrent miscarriage: Etiology and pregnancy outcome. J. Reprod. Immunol. 2017; 120: 42-7.
  54. Lee S.K., Na B.J., Kim J.Y., Hur S.E., Lee M., Gilman-Sachs A., Kwak-Kim J. Determination of clinical cellular immune markers in women with recurrent pregnancy loss. Am. J. Reprod. Immunol. 2013; 70(5): 398-411.
  55. Beer A.E., Kwak J.Y., Ruiz J.E. Immunophenotypic profiles of peripheral blood lymphocytes in women with recurrent pregnancy losses and in infertile women with multiple failed in vitro fertilization cycles. Am. J. Reprod. Immunol. 1996; 35(4): 376-82.

Received 21.12.2020

Accepted 12.01.2021

About the Authors

Valeriya A. Zagaynova, Postgraduate student of the Department of Assisted Reproductive Technologies, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology. E-mail: ORCID: 0000-0001-6971-7024. 199034, Mendeleevskaya line, 3, St. Petersburg, Russia.
Igor Yu. Kogan, Corresponding Member of RAS, MD, PhD, DSci (Medicine), Director of the D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology; Professor of the Department of Obstetrics, Gynecology and Reproductology, St. Petersburg State University. E-mail: ORCID: 0000-0002-7351-6900.
199034, Mendeleevskaya line, 3, St. Petersburg, Russia; 199034, Universitetskaya emb., 7, St. Petersburg, Russia.
Olesya N. Bespalova, MD, PhD, DSci (Medicine), Deputy Director, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology. E-mail:, ORCID: 0000-0002-6542-5953. 199034, Mendeleevskaya line, 3, St. Petersburg, Russia.
Sergey A. Selkov, Honored Scientist of the Russian Federation, Professor, Head of the Department of Immunology and Intercellular Interactions, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology. E-mail: ORCID: 0000-0003-1560-7529. 199034, Mendeleevskaya line, 3, St. Petersburg, Russia.
Dmitry I. Sokolov, DSci (Bio), Head of the Laboratory of Intercellular Interactions, Department of Immunology and Intercellular Interactions, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology. E-mail: ORCID: 0000-0002-5749-2531. 199034, Mendeleevskaya line, 3, St. Petersburg, Russia.

For citation: Zagainova V.A., Kogan I.Yu., Bespalova O.N., Selkov S.A., Sokolov D.I. The role of peripheral and endometrial natural killer cells in recurrent reproductive losses.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2021; 7: 19-27 (in Russian)

Similar Articles

By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.