{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:35:04Z","timestamp":1759970104042,"version":"build-2065373602"},"reference-count":75,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T00:00:00Z","timestamp":1736121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Pecs Medical School Research Grant","award":["KA-2024-09"],"award-info":[{"award-number":["KA-2024-09"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pregnancy involves significant immunological changes to support fetal development while protecting the mother from infections. A growing body of evidence supports the importance of immune checkpoint pathways, especially at the maternal\u2013fetal interface, although limited information is available about the peripheral expression of these molecules by CD8+ and CD8\u2212 NK cell subsets during the trimesters of pregnancy. Understanding the dynamics of these immune cells and their checkpoint pathways is crucial for elucidating their roles in pregnancy maintenance and potential complications. This study aims to investigate the peripheral expression and functional characteristics of CD8+ and CD8\u2212 NK cell subsets throughout pregnancy, providing insights into their contributions to maternal and fetal health. A total of 34 healthy women were enrolled from the first, 30 from the second and 40 from the third trimester of pregnancy. At the same time, 35 healthy age-matched non-pregnant women formed the control group. From peripheral blood, mononuclear cells were separated and stored at \u221280 \u00b0C. CD8+ and CD8\u2212 NK cell subsets were analyzed from freshly thawed samples, and surface and intracellular staining was performed using flow cytometric analyses. The proportions of CD56+ NK cells in peripheral blood were similar across groups. While CD8\u2212 NKdim cells increased significantly in all trimesters compared to non-pregnant controls, CD8+ NKdim cells showed no significant changes. CD8\u2212 NKbright cells had higher frequencies throughout pregnancy, whereas CD8+ NKbright cells significantly increased only in the first and second trimesters. The expression levels of immune checkpoint molecules, such as PD-1 and PD-L1, and cytotoxic-activity-related molecules were stable, with notable perforin and granzyme B increases in CD8\u2212 NKbright cells throughout pregnancy. Our study shows that peripheral NK cell populations, especially CD8\u2212 subsets, are predominant during pregnancy. This shift suggests a crucial role for CD8\u2212 NK cells in balancing maternal immune tolerance and surveillance. The stable expression of immune checkpoint molecules indicates that other regulatory mechanisms may be at work. These findings enhance our understanding of peripheral immune dynamics in pregnancy and suggest that targeting CD8\u2212 NKbright cell functions could help manage pregnancy-related immune complications. This research elucidates the stable distribution and functional characteristics of peripheral NK cells during pregnancy, with CD8\u2212 subsets being more prevalent. The increased activity of CD8\u2212 NKbright cells suggests their critical role in maintaining immune surveillance. Our findings provide a basis for future studies to uncover the mechanisms regulating NK cell function in pregnancy, potentially leading to new treatments for immune-related pregnancy complications.<\/jats:p>","DOI":"10.3390\/ijms26010428","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T09:17:02Z","timestamp":1736155022000},"page":"428","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD8+ and CD8\u2212 NK Cells and Immune Checkpoint Networks in Peripheral Blood During Healthy Pregnancy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9913-2024","authenticated-orcid":false,"given":"Matyas","family":"Meggyes","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical School, University of Pecs, 12 Szigeti Street, 7624 Pecs, Hungary"},{"name":"Janos Szentagothai Research Centre, 20 Ifjusag Street, 7624 Pecs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7742-4459","authenticated-orcid":false,"given":"David U.","family":"Nagy","sequence":"additional","affiliation":[{"name":"Institute of Geobotany\/Plant Ecology, Martin-Luther-University, Gro\u00dfe Steinstra\u00dfe 79\/80, D-06108 Halle, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Livia","family":"Mezosi","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical School, University of Pecs, 12 Szigeti Street, 7624 Pecs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8687-7430","authenticated-orcid":false,"given":"Beata","family":"Polgar","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical School, University of Pecs, 12 Szigeti Street, 7624 Pecs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1208-2969","authenticated-orcid":false,"given":"Laszlo","family":"Szereday","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical School, University of Pecs, 12 Szigeti Street, 7624 Pecs, Hungary"},{"name":"Janos Szentagothai Research Centre, 20 Ifjusag Street, 7624 Pecs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0165-0378(03)00083-4","article-title":"The Immunological Problem of Pregnancy: 50 Years with the Hope of Progress. A Tribute to Peter Medawar","volume":"60","author":"Billington","year":"2003","journal-title":"J. Reprod. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1056\/NEJMra1213566","article-title":"Pregnancy and Infection","volume":"370","author":"Kourtis","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/nm.3160","article-title":"Fetomaternal Immune Cross-Talk and Its Consequences for Maternal and Offspring\u2019s Health","volume":"99","author":"Arck","year":"2013","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Miko, E., Meggyes, M., Doba, K., Barakonyi, A., and Szereday, L. (2019). Immune Checkpoint Molecules in Reproductive Immunology. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00846"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/j.1600-0897.1997.tb00321.x","article-title":"Cytokine Production by Lymphocytes in Pregnancy","volume":"38","author":"Szereday","year":"1997","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Abu-Raya, B., Michalski, C., Sadarangani, M., and Lavoie, P.M. (2020). Maternal Immunological Adaptation During Normal Pregnancy. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.575197"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"76.7","DOI":"10.4049\/jimmunol.202.Supp.76.7","article-title":"LAG-3 Modulation of Natural Killer Cell Immunoregulatory Function","volume":"202","author":"Ali","year":"2019","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/s41590-018-0132-0","article-title":"Blockade of the Checkpoint Receptor TIGIT Prevents NK Cell Exhaustion and Elicits Potent Anti-Tumor Immunity","volume":"19","author":"Zhang","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.urolonc.2020.06.007","article-title":"TIM-3 and TIGIT Are Possible Immune Checkpoint Targets in Patients with Bladder Cancer","volume":"40","author":"Attalla","year":"2022","journal-title":"Urol. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.ejogrb.2020.06.031","article-title":"Investigation of Mucosal-Associated Invariant T (MAIT) Cells Expressing Immune Checkpoint Receptors (TIGIT and CD226) in Early-Onset Preeclampsia","volume":"252","author":"Meggyes","year":"2020","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Judge, S.J., Murphy, W.J., and Canter, R.J. (2020). Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence. Front. Cell Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.00049"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/s41577-021-00562-7","article-title":"NK Cells Seize PD1 from Leukaemia Cells","volume":"21","author":"Newman","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5520","DOI":"10.1158\/1078-0432.CCR-20-0575","article-title":"IL15 Stimulation with TIGIT Blockade Reverses CD155-Mediated NK-Cell Dysfunction in Melanoma","volume":"26","author":"Chauvin","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.coche.2017.11.006","article-title":"CD8+ T Cells and NK Cells: Parallel and Complementary Soldiers of Immunotherapy","volume":"19","author":"Rosenberg","year":"2018","journal-title":"Curr. Opin. Chem. Eng."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/ni.2032","article-title":"Natural Killer Cell Memory","volume":"12","author":"Paust","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.immuni.2015.09.013","article-title":"Natural Killer Cell Memory","volume":"43","author":"Sun","year":"2015","journal-title":"Immunity"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.it.2011.06.013","article-title":"Origin, Phenotype and Function of Human Natural Killer Cells in Pregnancy","volume":"32","author":"Vacca","year":"2011","journal-title":"Trends Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3913","DOI":"10.4049\/jimmunol.1001637","article-title":"Immature NK Cells, Capable of Producing Interleukin-22, Are Present in Human Uterine Mucosa","volume":"185","author":"Male","year":"2010","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Xie, M., Li, Y., Meng, Y.Z., Xu, P., Yang, Y.G., Dong, S., He, J., and Hu, Z. (2022). Uterine Natural Killer Cells: A Rising Star in Human Pregnancy Regulation. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.918550"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.it.2006.06.009","article-title":"NK Cells and Human Pregnancy\u2014An Inflammatory View","volume":"27","author":"Sargent","year":"2006","journal-title":"Trends Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.jri.2010.11.002","article-title":"Decidualization and Angiogenesis in Early Pregnancy: Unravelling the Functions of DC and NK Cells","volume":"88","author":"Blois","year":"2011","journal-title":"J. Reprod. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/cbin.11955","article-title":"Dominant Immune Cells in Pregnancy and Pregnancy Complications: T Helper Cells (TH1\/TH2, TH17\/Treg Cells), NK Cells, MDSCs, and the Immune Checkpoints","volume":"47","author":"Esparvarinha","year":"2023","journal-title":"Cell Biol. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e13667","DOI":"10.1111\/aji.13667","article-title":"Cytokines, NK Cells and Regulatory T Cell Functions in Normal Pregnancy and Reproductive Failures","volume":"89","author":"Rao","year":"2023","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cai, J.Y., Tang, Y.Y., Deng, X.H., Li, Y.J., Liang, G., Meng, Y.Q., and Zhou, H. (2022). Recurrent Implantation Failure May Be Identified by a Combination of Diagnostic Biomarkers: An Analysis of Peripheral Blood Lymphocyte Subsets. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.865807"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1111\/j.1365-2567.2005.02235.x","article-title":"Ligation of CD8alpha on Human Natural Killer Cells Prevents Activation-Induced Apoptosis and Enhances Cytolytic Activity","volume":"116","author":"Addison","year":"2005","journal-title":"Immunology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1046\/j.1365-3083.2001.00838.x","article-title":"The Phenotypic Heterogeneity of Human Natural Killer Cells: Presence of at Least 48 Different Subsets in the Peripheral Blood","volume":"53","author":"Jonges","year":"2001","journal-title":"Scand. J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/s41467-020-20594-2","article-title":"A CD8+ NK Cell Transcriptomic Signature Associated with Clinical Outcome in Relapsing Remitting Multiple Sclerosis","volume":"12","author":"McKinney","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12397","DOI":"10.1128\/JVI.01420-14","article-title":"High Frequencies of Polyfunctional CD8+ NK Cells in Chronic HIV-1 Infection Are Associated with Slower Disease Progression","volume":"88","author":"Ahmad","year":"2014","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Lucar, O., Keith Reeves, R., and Jost, S. (2019). A Natural Impact: NK Cells at the Intersection of Cancer and HIV Disease. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01850"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhang, X., and Wei, H. (2021). Role of Decidual Natural Killer Cells in Human Pregnancy and Related Pregnancy Complications. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.728291"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1111\/aji.12259","article-title":"Characterization of Uterine NK Cells in Women with Infertility or Recurrent Pregnancy Loss and Associated Endometriosis","volume":"72","author":"Giuliani","year":"2014","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Mahajan, D., Sharma, N.R., Kancharla, S., Kolli, P., Tripathy, A., Sharma, A.K., Singh, S., Kumar, S., Mohanty, A.K., and Jena, M.K. (2022). Role of Natural Killer Cells during Pregnancy and Related Complications. Biomolecules, 12.","DOI":"10.3390\/biom12010068"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"103209","DOI":"10.1016\/j.jri.2020.103209","article-title":"Natural Killer Cells in Recurrent Miscarriage: An Overview","volume":"142","author":"Guerrero","year":"2020","journal-title":"J. Reprod. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1093\/humrep\/det414","article-title":"Interventions to Improve Reproductive Outcomes in Women with Elevated Natural Killer Cells Undergoing Assisted Reproduction Techniques: A Systematic Review of Literature","volume":"29","author":"Polanski","year":"2014","journal-title":"Hum. Reprod."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1111\/j.1600-0897.2009.00790.x","article-title":"CD3-CD56+CD16+ Natural Killer Cells and Improvement of Pregnancy Outcome in IVF\/ICSI Failure after Additional IVIG-Treatment","volume":"63","author":"Heilmann","year":"2010","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"103189","DOI":"10.1016\/j.jri.2020.103189","article-title":"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","volume":"142","author":"Day","year":"2020","journal-title":"J. Reprod. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.jaci.2016.04.025","article-title":"Identification of a Subset of Human Natural Killer Cells Expressing High Levels of Programmed Death 1: A Phenotypic and Functional Characterization","volume":"139","author":"Pesce","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.1600-0897.2009.00792.x","article-title":"Inflammation and Implantation","volume":"63","author":"Dekel","year":"2010","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1177\/1933719108317253","article-title":"Macrophages and Pregnancy","volume":"15","author":"Mor","year":"2008","journal-title":"Reprod. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/j.1600-0897.2009.00696.x","article-title":"The Characterization of the Subpopulation of Suppressive B7H4+ Macrophages and the Subpopulation of CD25+ CD4+ and FOXP3+ Regulatory T-Cells in Decidua during the Secretory Cycle Phase, Arias Stella Reaction, and Spontaneous Abortion\u2014A Preliminary Report","volume":"61","author":"Wicherek","year":"2009","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.siny.2006.05.001","article-title":"Inflammation in Preterm and Term Labour and Delivery","volume":"11","author":"Romero","year":"2006","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1159\/000293766","article-title":"NK Cell Activity and Estrogen Hormone Levels during Normal Human Pregnancy","volume":"25","author":"Gabrilovac","year":"1988","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.bpobgyn.2020.07.013","article-title":"Immunology and the Immunological Response in Pregnancy","volume":"76","author":"Orefice","year":"2021","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ando, K., H\u00e9dou, J.J., Feyaerts, D., Han, X., Ganio, E.A., Tsai, E.S., Peterson, L.S., Verdonk, F., Tsai, A.S., and Mari\u0107, I. (2021). A Peripheral Immune Signature of Labor Induction. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.725989"},{"key":"ref_45","first-page":"1033","article-title":"Reference Intervals of Systemic Immune-Inflammation Index, Neutrophil-to-Lymphocyte Ratio, Lymphocyte-to-Monocyte Ratio, and Platelet-to-Lymphocyte Ratio during Normal Pregnancy in China","volume":"27","author":"Bai","year":"2023","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_46","first-page":"93","article-title":"C-Reactive Protein Is Involved in Natural Killer Cell-Mediated Lysis but Does Not Mediate Effector-Target Cell Recognition","volume":"61","author":"Baum","year":"1987","journal-title":"Immunology"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wisgalla, A., Ramien, C., Streitz, M., Schlickeiser, S., Lupu, A.R., Diemert, A., Tolosa, E., Arck, P.C., Bellmann-Strobl, J., and Siebert, N. (2022). Alterations of NK Cell Phenotype During Pregnancy in Multiple Sclerosis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.907994"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.imlet.2014.06.015","article-title":"Proinflammatory Status Influences NK Cells Subsets in the Elderly","volume":"162","author":"Campos","year":"2014","journal-title":"Immunol. Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"156455","DOI":"10.1016\/j.cyto.2023.156455","article-title":"NK Cells and the Profile of Inflammatory Cytokines in the Peripheral Blood of Patients with Advanced Carcinomas","volume":"174","author":"Saito","year":"2024","journal-title":"Cytokine"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1111\/aji.12074","article-title":"Evidence for a Role for the Adaptive Immune Response in Human Term Parturition","volume":"69","author":"Romero","year":"2013","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Motomura, K., Miller, D., Galaz, J., Liu, T.N., Romero, R., and Gomez-Lopez, N. (2023). The Effects of Progesterone on Immune Cellular Function at the Maternal-Fetal Interface and in Maternal Circulation. J. Steroid Biochem. Mol. Biol., 229.","DOI":"10.1016\/j.jsbmb.2023.106254"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/ni1582","article-title":"Functions of Natural Killer Cells","volume":"9","author":"Vivier","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e626","DOI":"10.1002\/mco2.626","article-title":"Natural Killer Cells in Cancer Immunotherapy","volume":"5","author":"Wang","year":"2024","journal-title":"MedComm"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s12985-024-02287-0","article-title":"Unraveling the Dynamic Mechanisms of Natural Killer Cells in Viral Infections: Insights and Implications","volume":"21","author":"Letafati","year":"2024","journal-title":"Virol. J."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Pontrelli, P., Rascio, F., Castellano, G., Grandaliano, G., Gesualdo, L., and Stallone, G. (2020). The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01454"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/cmi.2014.68","article-title":"The Integrative Roles of Chemokines at the Maternal-Fetal Interface in Early Pregnancy","volume":"11","author":"Du","year":"2014","journal-title":"Cell Mol. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Zhang, S., Ding, J., Zhang, Y., Liu, S., Yang, J., and Yin, T. (2022). Regulation and Function of Chemokines at the Maternal\u2013Fetal Interface. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.826053"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1111\/j.1600-0897.2008.00596.x","article-title":"Clinical Implication of Natural Killer Cells and Reproduction","volume":"59","year":"2008","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"906813","DOI":"10.1155\/2013\/906813","article-title":"Natural Killer Cells and Their Activation Status in Normal Pregnancy","volume":"2013","author":"Mosimann","year":"2013","journal-title":"Int. J. Reprod. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1111\/imm.12218","article-title":"The up Side of Decidual Natural Killer Cells: New Developments in Immunology of Pregnancy","volume":"141","author":"Siewiera","year":"2014","journal-title":"Immunology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1159\/000286238","article-title":"CD8\u2212 Natural Killer Cells Are Greatly Enriched in the Human Gastrointestinal Tract and Have the Capacity to Respond to Bacteria","volume":"2","author":"Lindgren","year":"2010","journal-title":"J. Innate Immun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1006\/cimm.1994.1262","article-title":"Estrogen Induces Suppression of Natural Killer Cell Cytotoxicity and Augmentation of Polyclonal B Cell Activation","volume":"158","author":"Nilsson","year":"1994","journal-title":"Cell Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Shah, N.M., Imami, N., and Johnson, M.R. (2018). Progesterone Modulation of Pregnancy-Related Immune Responses. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01293"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1002\/cyto.990110316","article-title":"Cytolytic Activity of Human Natural Killer Cell Subpopulations Isolated by Four-Color Immunofluorescence Flow Cytometric Cell Sorting","volume":"11","author":"Srour","year":"1990","journal-title":"Cytometry"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1016\/j.jid.2017.03.025","article-title":"Increased Soluble CD226 in Sera of Patients with Cutaneous T-Cell Lymphoma Mediates Cytotoxic Activity against Tumor Cells via CD155","volume":"137","author":"Takahashi","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.rbmo.2010.07.012","article-title":"Possible Role of Natural Killer and Natural Killer T-like Cells in Implantation Failure after IVF","volume":"21","author":"Miko","year":"2010","journal-title":"Reprod. Biomed. Online"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.imbio.2014.11.015","article-title":"Accentuated Hypo- and Hyper-NK Lymphocyte CD8 Expression Is a Marker of NK Subsets\u2019 Misbalance and Is Predictive for Reproductive Failures","volume":"220","year":"2015","journal-title":"Immunobiology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5879","DOI":"10.1128\/jvi.67.10.5879-5888.1993","article-title":"Differential Replication of Human Immunodeficiency Virus Type 1 in CD8\u2212 and CD8+ Subsets of Natural Killer Cells: Relationship to Cytokine Production Pattern","volume":"67","author":"Toth","year":"1993","journal-title":"J. Virol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Zhou, J., Yan, P., Ma, W., and Li, J. (Cytokine Growth Factor. Rev., 2024). Cytokine Modulation and Immunoregulation of Uterine NK Cells in Pregnancy Disorders, Cytokine Growth Factor. Rev., in press.","DOI":"10.1016\/j.cytogfr.2024.11.007"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Fu, W., Cai, R., Ma, Z., Li, T., Lei, C., Zhao, J., and Hu, S. (2021). TIGIT-Fc as a Potential Therapeutic Agent for Fetomaternal Tolerance. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.649135"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"107935","DOI":"10.1016\/j.intimp.2021.107935","article-title":"Immune Checkpoints and Reproductive Immunology: Pioneers in the Future Therapy of Infertility Related Disorders?","volume":"99","author":"Parhizkar","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Pantos, K., Grigoriadis, S., Maziotis, E., Pistola, K., Xystra, P., Pantou, A., Kokkali, G., Pappas, A., Lambropoulou, M., and Sfakianoudis, K. (2022). The Role of Interleukins in Recurrent Implantation Failure: A Comprehensive Review of the Literature. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042198"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Ling, Q., Xu, J., Tian, Y., Chen, D., Mo, C., and Peng, B. (2024). Effect of IVIG Therapy on Pregnant Women with Unexplained Recurrent Spontaneous Abortion: A Systematic Review and Meta-Analysis. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1381461"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Meggyes, M., Nagy, D.U., Feik, T., Boros, A., Polgar, B., and Szereday, L. (2022). Examination of the TIGIT-CD226-CD112-CD155 Immune Checkpoint Network during a Healthy Pregnancy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810776"},{"key":"ref_75","unstructured":"Michael, J. (2021, June 08). Crawley Statistics: An Introduction Using R. Available online: https:\/\/www.wiley.com\/en-al\/Statistics%3A+An+Introduction+Using+R%2C+2nd+Edition-p-9781118941096."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/428\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:23:47Z","timestamp":1759919027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/428"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,6]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ijms26010428"],"URL":"https:\/\/doi.org\/10.3390\/ijms26010428","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,1,6]]}}}