Changes in expression of Ki-67, CD16 and CD56 by natural killer cells from peripheral blood mononuclear cells in the setting of recurrent miscarriage after in vitro culturing in the presence of trophoblast cells and IL-2.

Anacker J, Segerer SE, Hagemann C, Feix S, Kapp M, Bausch R, Kammerer U (2011) Human decidua and invasive trophoblasts are rich sources of nearly all human matrix metalloproteinases. Mol Hum Reprod 17:637–652. https://doi.org/10.1093/molehr/gar033 Becknell B, Caligiuri MA (2005) Interleukin-2, interleukin-15, and their roles in human natural killer cells. Adv Immunol 86:209–239. https://doi.org/10.1016/S0065-2776(04)86006-1 Beer AE, Kwak JY, Ruiz JE (1996) 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 35:376–382 Boyum A (1968) Separation of leukocytes from blood and bone marrow.Introduction. Scand J Clin Lab Invest Suppl 97:7 Carlino C, Stabile H, Morrone S, Bulla R, Soriani A, Agostinis C, Bossi F, Mocci C, Sarazani F, Tedesco F, Santoni A, Gismondi A (2008) Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy. Blood 111:3108–3115. https://doi.org/10.1182/blood-2007-08-105965 Chiesa M, Pesce S, Muccio L, Carlomagno S, Sivori S, Moretta A, Marcenaro E (2016) Features of Memory-Like and PD-1(+) Human NK Cell Subsets. Front Immunol 7:351. https://doi.org/10.3389/fimmu.2016.00351 Chiossone L, Vacca P, Orecchia P, Croxatto D, Damonte P, Astigiano S, Barbieri O, Bottino C, Moretta L, Mingari MC (2014) In vivo generation of decidual natural killer cells from resident hematopoietic progenitors. Haematologica 99:448–457. https://doi.org/10.3324/haematol.2013.091421 DeMarco RA, Fink MP, Lotze MT (2005) Monocytes promote natural killer cell interferon gamma production in response to the endogenous danger signal HMGB1. Mol Immunol 42:433–444. https://doi.org/10.1016/j.molimm.2004.07.023 El Hachem H, Crepaux V, May-Panloup P, Descamps P, Legendre G, Bouet PE (2017) Recurrent pregnancy loss: current perspectives. Int J Womens Health 9:331–345. https://doi.org/10.2147/IJWH.S100817 Elkarhat Z, Kindil Z, Zarouf L, Razoki L, Aboulfaraj J, Elbakay C, Nassereddine S, Nasser B, Barakat A, Rouba H (2018) Chromosomal abnormalities in couples with recurrent spontaneous miscarriage: a 21-year retrospective study, a report of a novel insertion, and a literature review. J Assist Reprod Genet. https://doi.org/10.1007/s10815-018-1373-4 Farag SS, Caligiuri MA (2006) Human natural killer cell development and biology. Blood Rev 20:123–137. https://doi.org/10.1016/j.blre.2005.10.001 Fehniger TA, Cooper MA, Nuovo GJ, Cella M, Facchetti F, Colonna M, Caligiuri MA (2003) CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 101:3052–3057. https://doi.org/10.1182/blood-2002-09-2876 Giuliani E, Parkin KL, Lessey BA, Young SL, Fazleabas AT (2014) Characterization of uterine NK cells in women with infertility or recurrent pregnancy loss and associated endometriosis. Am J Reprod Immunol 72:262–269. https://doi.org/10.1111/aji.12259 Hakam MS, Miranda-Sayago JM, Hayrabedyan S, Todorova K, Spencer PS, Jabeen A, Barnea ER, Fernandez N (2017) Preimplantation factor (PIF) promotes HLA-G, -E, -F, -C expression in JEG-3 choriocarcinoma cells and endogenous progesterone activity. Cell Physiol Biochem 43:2277–2296. https://doi.org/10.1159/000484378 Higuma-Myojo S, Sasaki Y, Miyazaki S, Sakai M, Siozaki A, Miwa N, Saito S (2005) Cytokine profile of natural killer cells in early human pregnancy. Am J Reprod Immunol 54:21–29. https://doi.org/10.1111/j.1600-0897.2005.00279.x Hirakawa M, Matos TR, Liu H, Koreth J, Kim HT, Paul NE, Murase K, Whangbo J, Alho AC, Nikiforow S, Cutler C, Ho VT, Armand P, Alyea EP, Antin JH, Blazar BR, Lacerda JF, Soiffer RJ, Ritz J (2016) Low-dose IL-2 selectively activates subsets of CD4 + Tregs and NK cells. JCI Insight 1:e89278. https://doi.org/10.1172/jci.insight.89278 Homer HA (2018) Modern management of recurrent miscarriage. Aust N Z J Obstet Gynaecol. https://doi.org/10.1111/ajo.12920 King K, Smith S, Chapman M, Sacks G (2010) Detailed analysis of peripheral blood natural killer (NK) cells in women with recurrent miscarriage. Hum Reprod 25:52–58. https://doi.org/10.1093/humrep/dep349 Kohler PO, Bridson WE (1971) Isolation of hormone-producing clonal lines of human choriocarcinoma. J Clin Endocrinol Metab 32:683–687. https://doi.org/10.1210/jcem-32-5-683 Kondadasula SV, Varker KA, Lesinski GB, Benson DM Jr, Lehman A, Olencki T, Monk JP, Kendra K, Carson WE 3rd (2008) Activation of extracellular signaling regulated kinase in natural killer cells and monocytes following IL-2 stimulation in vitro and in patients undergoing IL-2 immunotherapy: analysis via dual parameter flow-cytometric assay. Cancer Immunol Immunother 57:1137–1149. https://doi.org/10.1007/s00262-007-0444-7 Kuon RJ, Vomstein K, Weber M, Muller F, Seitz C, Wallwiener S, Strowitzki T, Schleussner E, Markert UR, Daniel V, Toth B (2017) The “killer cell story” in recurrent miscarriage: association between activated peripheral lymphocytes and uterine natural killer cells. J Reprod Immunol 119:9–14. https://doi.org/10.1016/j.jri.2016.11.002 Kwak-Kim J, Bao S, Lee SK, Kim JW, Gilman-Sachs A (2014) Immunological modes of pregnancy loss: inflammation, immune effectors, and stress. Am J Reprod Immunol 72:129–140. https://doi.org/10.1111/aji.12234 Lashley LE, van der Hoorn ML, van der Mast BJ, Tilburgs T, van der Lee N, van der Keur C, van Beelen E, Roelen DL, Claas FH, Scherjon SA (2011) Changes in cytokine production and composition of peripheral blood leukocytes during pregnancy are not associated with a difference in the proliferative immune response to the fetus. Hum Immunol 72:805–811. https://doi.org/10.1016/j.humimm.2011.05.027 Laskarin G, Medancic SS, Redzovic A, Duric D, Rukavina D (2012) Specific decidual CD14(+) cells hamper cognate NK cell proliferation and cytolytic mediator expression after mucin 1 treatment in vitro. J Reprod Immunol 95:36–45. https://doi.org/10.1016/j.jri.2012.06.002 Mardanian F, Kazeroonizadeh M, Rashidi B (2015) Evaluation of CD56(dim) and CD56(bright) natural killer cells in peripheral blood of women with IVF failures. Iran J Reprod Med 13:577–582 Martinez-Zamora MA, Cervera R, Balasch J (2012) Recurrent miscarriage, antiphospholipid antibodies and the risk of thromboembolic disease. Clin Rev Allergy Immunol 43:265–274. https://doi.org/10.1007/s12016-012-8316-0 Mikhailova VA, Bazhenov DO, Belikova ME, Viknyanshchuk AN, Kogan IY, Sel’kov SA, Sokolov DI (2018) Interactions of NK cells and trophoblast cells. Methodological aspects. Bull Exp Biol Med 165:548–553. https://doi.org/10.1007/s10517-018-4212-9 Mikhaylova VA, Ovchinnikova OM, Onohina YS, Chugunova AA, Zainulina MS, Selkov SA, Sokolov DI (2014) Functional activity of peripheral blood NK-cells at preeclampsia Immunology (Russia). Immunologiya. 35:4–8 Ntrivalas EI, Kwak-Kim JY, Gilman-Sachs A, Chung-Bang H, Ng SC, Beaman KD, Mantouvalos HP, Beer AE (2001) Status of peripheral blood natural killer cells in women with recurrent spontaneous abortions and infertility of unknown aetiology. Hum Reprod 16:855–861. https://doi.org/10.1093/humrep/16.5.855 Papamitsou T, Toskas A, Papadopoulou K, Sioga A, Lakis S, Chatzistamatiou M, Economou Z, Adriopoulou L (2014) Immunohistochemical study of immunological markers: HLAG, CD16, CD25, CD56 and CD68 in placenta tissues in recurrent pregnancy loss. Histol Histopathol 29:1047–1055. https://doi.org/10.14670/HH-29.1047 Park SY, Yun S, Ryu BJ, Han AR, Lee SK (2017) Trophoblasts regulate natural killer cells via control of interleukin-15 receptor signaling. Am J Reprod Immunol. https://doi.org/10.1111/aji.12628 Senthilnayagam B, Karthikeyan S, Sukumaran J, Srivalsan A, Rao R, Subbiah V (2016) Decidual CD56+ natural killer cells in spontaneous early pregnancy loss—an immunohistochemical study. J Clin Diagn Res 10:EC27–EC29. https://doi.org/10.7860/jcdr/2016/22902.8740 Sharma S, Godbole G, Modi D (2016) Decidual Control of Trophoblast Invasion. Am J Reprod Immunol 75:341–350. https://doi.org/10.1111/aji.12466 Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL (2009) Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol 174:1959–1971. https://doi.org/10.2353/ajpath.2009.080995 Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA (2006) Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci USA 103:2788–2793. https://doi.org/10.1073/pnas.0511161103 Tang AW, Alfirevic Z, Quenby S (2011) Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review. Hum Reprod 26:1971–1980. https://doi.org/10.1093/humrep/der164 Ticconi C, Giuliani E, Sorge R, Patrizi L, Piccione E, Pietropolli A (2016) Gestational age of pregnancy loss in women with unexplained recurrent miscarriage. J Obstet Gynaecol Res 42:239–245. https://doi.org/10.1111/jog.12903 Wallace AE, Fraser R, Cartwright JE (2012) Extravillous trophoblast and decidual natural killer cells: a remodelling partnership. Hum Reprod Update 18:458–471. https://doi.org/10.1093/humupd/dms015 Wang S, Li YP, Ding B, Zhao YR, Chen ZJ, Xu CY, Fu YB, Wang XT (2014) Recurrent miscarriage is associated with a decline of decidual natural killer cells expressing killer cell immunoglobulin-like receptors specific for human leukocyte antigen C. J Obstet Gynaecol Res 40:1288–1295. https://doi.org/10.1111/jog.12329 Zhang Y, Qu D, Sun J, Zhao L, Wang Q, Shao Q, Kong B, Zhang Y, Qu X (2016) Human trophoblast cells induced MDSCs from peripheral blood CD14(+) myelomonocytic cells via elevated levels of CCL2. Cell Mol Immunol 13:615–627. https://doi.org/10.1038/cmi.2015.41 Zhang J, Dunk CE, Kwan M, Jones RL, Harris LK, Keating S, Lye SJ (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. https://doi.org/10.1038/cmi.2015.66

The authors express their gratitude to A.N. Viknianshchuk and E.A. Mikhailova for their technical assistance in obtaining the experimental data. Funding The research was supported by the Grant of the President of the Russian Federation for government support of the leading scientific schools of the Russian Federation (Grant No. NSh-2873.2018.7. Assessment of NK Cell Proliferation to Trophoblast Cells). The research was partially carried out within the framework of the government Program No. AAAA-A19-119021290116-1 (cell culturing). Author information Authors and Affiliations Corresponding author Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions About this article Cite this article Mikhailova, V.A., Khokhlova, E.V., Bazhenov, D.O. et al. Changes in expression of Ki-67, CD16 and CD56 by natural killer cells from peripheral blood mononuclear cells in the setting of recurrent miscarriage after in vitro culturing in the presence of trophoblast cells and IL-2. Cytotechnology 71, 861–871 (2019). https://doi.org/10.1007/s10616-019-00331-4 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s10616-019-00331-4