Preview

Medical Immunology (Russia)

Advanced search

Expression features of CD16 and NKG2D receptors by NK cells, NKT cells and T lymphocytes of peripheral blood associated with female infertility

https://doi.org/10.15789/1563-0625-EFO-2944

Abstract

The increasing incidence of infertility determines relevance of studying various cellular factors, including immune cells, in pathogenesis of this disorder. In cases of infertility, some changes are described in NK cell activation in decidual and peripheral blood cells, as well as in representation of NKT cells and T lymphocytes in uterus at miscarriage (MC). NK cells and NKT cells are characterized by expression of activating receptor NKG2D and a receptor for immunoglobulin G Fc-region CD16. Distinct populations of T lymphocytes express NKG2D. The aim of the present study was to analyze the expression of CD16 and NKG2D by NK cells, NKT cells and NKG2D receptor by peripheral blood T lymphocytes. We examined 60 women with infertility. The control group consisted of healthy non-pregnant fertile women (n = 17). Mononuclear cells were obtained from peripheral blood and treated with monoclonal antibodies to CD45, CD14, CD3, CD56, CD16, NKG2D. The intensity of NKG2D receptor expression on peripheral blood NKT cells in patients with primary infertility proved to be lower than in healthy non-pregnant fertile women. This difference may be caused by the absence of an embryo implantation in previous history of primary infertility and, accordingly, lacking influence of cytokines and cellular microenvironment specific for first trimester of pregnancy. In patients with secondary infertility and miscarriage (MC), the relative numbers of CD16+NK cells and CD16+NKG2D-NK cells in peripheral blood were reduced when compared to the women with secondary infertility without history of MC. Relative numbers of CD16+NK cells and CD16+NKG2D-NK cells in peripheral blood were also reduced in patients with secondary infertility and MC compared to patients with primary infertility and to healthy non-pregnant fertile women. CD16 expression intensity of NK cells was shown to be reduced in subgroup of women with secondary infertility and a history of MC compared to control group and to women with secondary infertility without a history of MC. No differences in NKG2D expression by T lymphocytes associated with infertility were found. Reduced CD16 expression by NK cells of women with secondary infertility and MC may reflect the impaired functional differentiation of NK cells associated with this condition.

About the Authors

V. A. Mikhailova
D. Ott Research Institute for Obstetrics, Gynecology and Reproductology
Russian Federation

Mikhailova Valentina A., PhD, MD (Biology), Leading Researcher, Laboratory of Intercellular Interactions, Department of Immunology and Intercellular Interactions

St. Petersburg



A. A. Davydova
D. Ott Research Institute for Obstetrics, Gynecology and Reproductology
Russian Federation

Davydova Alina A., Junior Researcher, Laboratory of Intercellular Interactions, Department of Immunology and Intercellular Interactions

St. Petersburg



V. A. Zagaynova
D. Ott Research Institute for Obstetrics, Gynecology and Reproductology
Russian Federation

Zagaynova Valeria A., Obstetrician-Gynecologist, Department of Assisted Reproductive Technologies

St. Petersburg



O. B. Marko
D. Ott Research Institute for Obstetrics, Gynecology and Reproductology
Russian Federation

Marko Oksana B., Junior Researcher, Laboratory of Intercellular Interactions, Department of Immunology and Intercellular Interactions

St. Petersburg



E. R. Mkrtchyan
D. Ott Research Institute for Obstetrics, Gynecology and Reproductology
Russian Federation

Mkrtchyan Edgar R., Laboratory Assistant, Laboratory of Intercellular Interactions, Department of Immunology and Intercellular Interactions

St. Petersburg



A. S. Zhguleva
D. Ott Research Institute for Obstetrics, Gynecology and Reproductology
Russian Federation

Zhguleva Aleksandra S., Laboratory Assistant, Laboratory of Intercellular Interactions, Department of Immunology and Intercellular Interactions

St. Petersburg



O. A. Bakulina
D. Ott Research Institute for Obstetrics, Gynecology and Reproductology
Russian Federation

Bakulina Olga A., Laboratory Assistant, Laboratory of Intercellular Interactions, Department of Immunology and Intercellular Interactions

St. Petersburg



S. A. Selkov
D. Ott Research Institute for Obstetrics, Gynecology and Reproductology
Russian Federation

Selkov Sergey A., PhD, MD (Medicine), Professor, Honored Scientist of the Russian Federation, Chief Researcher, Department of Immunology and Intercellular Interactions

St. Petersburg



O. N. Bespalova
D. Ott Research Institute for Obstetrics, Gynecology and Reproductology
Russian Federation

Bespalova Olesya N., PhD, MD (Medicine), Deputy Director for Research

St. Petersburg



D. I. Sokolov
D. Ott Research Institute for Obstetrics, Gynecology and Reproductology
Russian Federation

Sokolov Dmitry I., PhD, MD (Biology), Head, Department of Immunology and Intercellular Interactions

St. Petersburg

 



References

1. Barinova E.K., Arutin D.G. Infertility predictors. Akusherstvo i ginekologiya = Obstetrics and Gynecology, 2023, Vol. 4, pp. 178-183. (In Russ.)

2. Zagaynova V.A., Kogan I.Yu., Selkov S.A., Bespalova O.N., Krikheli I.O., Mikhailova V.A., Davydova A.A., Milyutina Yu. P., Sokolov D.I. Peripheral blood NK cells in women with unsuccessful attempts of assisted reproduction: quantity, subpopulation composition and activation markers. Akusherstvo i ginekologiya = Obstetrics and Gynecology, 2022, Vol. 9, pp. 102-113. (In Russ.)

3. Osmanov E.M., Prokopov A.Yu. Medical-biological and social significance of female infertility. Meditsina i fizicheskaya kultura: nauka i praktika = Medicine and Physical Education: Science and Practice, 2020, Vol. 2, no. 1 (5), pp. 29-38. (In Russ.)

4. Strizhova T.V. Key issues of assessing infertile patients. Klinicheskiy razbor v akusherstve, ginekologii i reproduktologii = Clinical Analysis in Obstetrics, Gynecology and Reproductology, 2022, Vol. 1, no. 2, pp. 32-38. (In Russ.)

5. Braun A.S., Vomstein K., Reiser E., Tollinger S., Kyvelidou C., Feil K., Toth B. NK and T cell subtypes in the endometrium of patients with recurrent pregnancy loss and recurrent implantation failure: implications for pregnancy success. J. Clin. Med., 2023, Vol. 12, no. 17, 5585. doi: 10.3390/jcm12175585.

6. Chin D.S., Lim C.S.Y., Nordin F., Arifin N., Jun T.G. Antibody-dependent cell-mediated cytotoxicity through Natural Killer (NK) cells: Unlocking NK cells for future immunotherapy. Curr. Pharm. Biotechnol., 2022, Vol. 23, no. 4, pp. 552-578.

7. Euchner J., Sprissler J., Cathomen T., Furst D., Schrezenmeier H., Debatin K.M., Schwarz K., Felgentreff K. Natural killer cells generated from human induced pluripotent stem cells mature to CD56(bright)CD16(+) NKp80(+/-)In-Vitro and Express KIR2DL2/DL3 and KIR3DL1. Front. Immunol., 2021, Vol. 12, 640672. doi: 10.3389/fimmu.2021.640672.

8. Gamliel M., Goldman-Wohl D., Isaacson B., Gur C., Stein N., Yamin R., Berger M., Grunewald M., Keshet E., Rais Y., Bornstein C., David E., Jelinski A., Eisenberg I., Greenfield C., Ben-David A., Imbar T., Gilad R., HaimovKochman R., Mankuta D., Elami-Suzin M., Amit I., Hanna J.H., Yagel S., Mandelboim O. Trained memory of human uterine NK cells enhances their function in subsequent pregnancies. Immunity, 2018, Vol. 48, no. 5, pp. 951-962.e5.

9. Godfrey D.I., MacDonald H.R., Kronenberg M., Smyth M.J., van Kaer L. NKT cells: what’s in a name? Nat. Rev. Immunol., 2004, Vol. 4, no. 3, pp. 231-237.

10. Habets D.H.J., Schlutter A., van Kuijk S.M.J., Spaanderman M.E.A., 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, Vol. 88, no. 5, e13612.

11. Hosseini S., Shokri F., Pour S.A., Khoshnoodi J., Jeddi-Tehrani M., Zarnani A.H. Diminished frequency of menstrual and peripheral blood NKT-like cells in patients with unexplained recurrent spontaneous abortion and infertile women. Reprod. Sci., 2019, Vol. 26, no. 1, pp. 97-108.

12. Hromadnikova I., Li S., Kotlabova K., Dickinson A.M. 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 on peripheral blood T Cells, B Cells and NKT Cells. PLoS One, 2016, Vol. 11, no. 3, e0151535. doi: 10.1371/journal.pone.0151535.

13. Huang C., Xiang Z., Zhang Y., Li Y., Xu J., Zhang H., Zeng Y., Tu W. NKG2D as a cell surface marker on gammadelta-T cells for predicting pregnancy outcomes in patients with unexplained repeated implantation failure. Front. Immunol., 2021, Vol. 12, 631077. doi: 10.3389/fimmu.2021.631077.

14. Jafarpour R., Pashangzadeh S., Mehdizadeh S., Bayatipoor H., Shojaei Z., Motallebnezhad M. Functional significance of lymphocytes in pregnancy and lymphocyte immunotherapy in infertility: A comprehensive review and update. Int. Immunopharmacol., 2020, Vol. 87, 106776. doi: 10.1016/j.intimp.2020.106776.

15. Keskin D.B., Allan D.S., Rybalov B., Andzelm M.M., Stern J.N., Kopcow H.D., Koopman L.A., Strominger J.L. TGFbeta promotes conversion of CD16+ peripheral blood NK cells into CD16- NK cells with similarities to decidual NK cells. Proc. Natl. Acad. Sci. USA, 2007, Vol. 104, no. 9, pp. 3378-3383.

16. Laskarin G., Strbo N., Crncic T.B., Juretic K., Bataille N.L., Chaouat G., Rukavina D. Physiological role of IL-15 and IL-18 at the maternal-fetal interface. Chem. Immunol. Allergy, 2005, Vol. 89, pp. 10-25.

17. Lee S.K., Kim C.J., Kim D.J., Kang J.H. Immune cells in the female reproductive tract. Immune Netw., 2015, Vol. 15, no. 1, pp. 16-26.

18. Liu J., Song G., Lin X., Pang X., Meng T. Upregulated unique long 16 binding protein 1 detected in preeclamptic placenta affects human extravillous trophoblast cell line (HTR-8/SVneo) invasion by modulating the function of uterine natural killer cells. Exp. Ther. Med., 2017, Vol. 13, no. 4, pp. 1447-1455.

19. Liu M., Meng Y., Zhang L., Han Z., Feng X. High-efficient generation of natural killer cells from peripheral blood with preferable cell vitality and enhanced cytotoxicity by combination of IL-2, IL-15 and IL-18. Biochem. Biophys. Res. Commun., 2021, Vol. 534, pp. 149-156.

20. Marlin R., Duriez M., Berkane N., de Truchis C., Madec Y., Rey-Cuille M.A., Cummings J.S., Cannou C., Quillay H., Barre-Sinoussi F., Nugeyre M.T., Menu E. Dynamic shift from CD85j/ILT-2 to NKG2D NK receptor expression pattern on human decidual NK during the first trimester of pregnancy. PLoS One, 2012, Vol. 7, no. 1, e30017. doi: 10.1371/journal.pone.0030017.

21. 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, Vol. 19, no. 1, 74. doi: 10.1186/s12884-019-2218-6.

22. Meggyes M., Nagy D.U., Saad Al Deen I., Parkanyi B., Szereday L. CD8+ and CD8- NKT Cells Exhibit Phenotypic Changes During Pregnancy. Immunol. Invest., 2023, Vol. 52, no. 1, pp. 35-51.

23. Moffett A., Shreeve N. First do no harm: uterine natural killer (NK) cells in assisted reproduction. Hum. Reprod., 2015, Vol. 30, no. 7, pp. 1519-1525.

24. Molfetta R., Quatrini L., Santoni A., Paolini R. Regulation of NKG2D-Dependent NK cell functions: the yin and the yang of receptor endocytosis. Int. J. Mol. Sci., 2017, Vol. 18, no. 8, 1677. doi: 10.3390/ijms18081677.

25. Pathare A.D.S., Loid M., Saare M., Gidlof S.B., Zamani Esteki M., Acharya G., Peters M., Salumets A. Endometrial receptivity in women of advanced age: an underrated factor in infertility. Hum. Reprod. Update, 2023, Vol. 29, no. 6, pp. 773-793.

26. Quatrini L., Della Chiesa M., Sivori S., Mingari M.C., Pende D., Moretta L. Human NK cells, their receptors and function. Eur. J. Immunol., 2021, Vol. 51, no. 7, pp. 1566-1579.

27. Rao V.A., Kurian N.K., Rao K.A. Cytokines, NK cells and regulatory T cell functions in normal pregnancy and reproductive failures. Am. J. Reprod. Immunol., 2023, Vol. 89, no. 2, e13667. doi: 10.1111/aji.13667.

28. Sacks G., Yang Y., Gowen E., Smith S., Fay L., Chapman M. Detailed analysis of peripheral blood natural killer cells in women with repeated IVF failure. Am. J. Reprod. Immunol., 2012, Vol. 67, no. 5, pp. 434-442.

29. Santillan I., Lozano I., Illan J., Verdu 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, Vol. 108, pp. 142-148.

30. Seshadri S., Sunkara S.K. Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis. Hum. Reprod. Update, 2014, Vol. 20, no. 3, pp. 429-438.

31. Sharma S., Godbole G., Modi D. Decidual control of trophoblast invasion. Am. J. Reprod. Immunol., 2016, Vol. 75, no. 3, pp. 341-350.

32. Shojaei Z., Jafarpour R., Mehdizadeh S., Bayatipoor H., Pashangzadeh S., Motallebnezhad M. Functional prominence of natural killer cells and natural killer T cells in pregnancy and infertility: A comprehensive review and update. Pathol. Res. Pract., 2022, Vol. 238, 154062. doi: 10.1016/j.prp.2022.154062.

33. Somigliana E., Li Piani L., Paffoni A., Salmeri N., Orsi M., Benaglia L., Vercellini P., Vigano P. Endometriosis and IVF treatment outcomes: unpacking the process. Reprod. Biol. Endocrinol., 2023, Vol. 21, no. 1, pp. 107-118.

34. Sunkara S.K., Kamath M.S., Pandian Z., Gibreel A., Bhattacharya S. In vitro fertilisation for unexplained subfertility. Cochrane Database Syst. Rev., 2023, Vol. 9, no. 9, CD003357. doi: 10.1002/14651858.CD003357.pub5.

35. Tsuda H., Sakai M., Michimata T., Tanebe K., Hayakawa S., Saito S. Characterization of NKT cells in human peripheral blood and decidual lymphocytes. Am. J. Reprod. Immunol., 2001, Vol. 45, no. 5, pp. 295-302.

36. Vacca P., Cantoni C., Prato C., Fulcheri E., Moretta A., Moretta L.,Mingari M.C. Regulatory role of NKp44, NKp46, DNAM-1 and NKG2D receptors in the interaction between NK cells and trophoblast cells. Evidence for divergent functional profiles of decidual versus peripheral NK cells. Int. Immunol., 2008, Vol. 20, no. 11, pp. 1395-1405.

37. van den Heuvel M.J., Peralta C.G., Hatta K., Han V.K., Clark D.A. Decline in number of elevated blood CD3(+) CD56(+) NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy. Am. J. Reprod. Immunol., 2007, Vol. 58, no. 5, pp. 447-459.

38. Vomstein K., Egerup P., Kolte A.M., Behrendt-Moller I., Boje A.D., Bertelsen M.L., Eiken C.S., Reiersen M.R., Toth B., la Cour Freiesleben N., Nielsen H.S. Biopsy-free profiling of the uterine immune system in patients with recurrent pregnancy loss and unexplained infertility. Reprod. Biomed. Online, 2023, Vol. 47, no. 2, 103207. doi: 10.1016/j.rbmo.2023.03.018.

39. Wallace A.E., Goulwara S.S., Whitley G.S., Cartwright J.E. Oxygen modulates human decidual natural killer cell surface receptor expression and interactions with trophoblasts. Biol. Reprod., 2014, Vol. 91, no. 6, pp. 134-140.

40. Wang C., Zhao X., Zhang H., Bing Z., Wu Y., Li R., Yang Y., Yang K. Comprehensive analysis of immunerelated genes associated with the microenvironment of patients with unexplained infertility. Ann. Transl. Med., 2023, Vol. 11, no. 2, pp. 84-105.

41. Whettlock E.M., Woon E.V., Cuff A.O., Browne B., Johnson M.R., Male V. Dynamic changes in uterine NK cell subset frequency and function over the menstrual cycle and pregnancy. Front. Immunol., 2022, Vol. 13, 880438. doi: 10.3389/fimmu.2022.880438.

42. Wu X., Sharma A., Oldenburg J., Weiher H., Essler M., Skowasch D., Schmidt-Wolf I.G.H. NKG2D engagement alone is sufficient to activate cytokine-induced killer cells while 2B4 only provides limited coactivation. Front. Immunol., 2021, Vol. 12, 731767. doi: 10.3389/fimmu.2021.731767.

43. Xiao H., Lin R., Chen C., Lian R., Wu Y., Diao L., Yin T., Huang C. gammadelta-T cell with high toxic potential was associated with recurrent miscarriage. Am. J. Reprod. Immunol., 2023, Vol. 90, no. 1, e13717. doi: 10.1111/aji.13717.

44. Yamamoto T., Takahashi Y., Kase N., Mori H. Proportion of CD56+3+ T cells in decidual and peripheral lymphocytes of normal pregnancy and spontaneous abortion with and without history of recurrent abortion. Am. J. Reprod. Immunol., 1999, Vol. 42, no. 6, pp. 355-360.

45. Yang H.L., Zhou W.J., Lu H., Lei S.T., Ha S.Y., Lai Z.Z., Zheng Z.M., Ruan L.Y., He Y.Y., Li D.J., Li M.Q., Shao J. Decidual stromal cells promote the differentiation of CD56(bright) CD16(-) NK cells by secreting IL-24 in early pregnancy. Am. J. Reprod. Immunol., 2019, Vol. 81, no. 6, e13110. doi: 10.1111/aji.13110.

46. Zhao J., Huang B., Li N., Wang X., Xu B., Li Y. Relationship between advanced maternal age and decline of endometrial receptivity: a systematic review and meta-analysis. Aging (Albany NY), 2023, Vol. 15, no. 7, pp. 2460-2472.


Supplementary files

Review

For citations:


Mikhailova V.A., Davydova A.A., Zagaynova V.A., Marko O.B., Mkrtchyan E.R., Zhguleva A.S., Bakulina O.A., Selkov S.A., Bespalova O.N., Sokolov D.I. Expression features of CD16 and NKG2D receptors by NK cells, NKT cells and T lymphocytes of peripheral blood associated with female infertility. Medical Immunology (Russia). 2025;27(4):789-802. (In Russ.) https://doi.org/10.15789/1563-0625-EFO-2944

Views: 428


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 1563-0625 (Print)
ISSN 2313-741X (Online)