{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:47:57Z","timestamp":1790650077198,"version":"4.1.0"},"reference-count":58,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T00:00:00Z","timestamp":1723680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Investigator Award","doi-asserted-by":"publisher","award":["094073\/Z\/10\/Z"],"award-info":[{"award-number":["094073\/Z\/10\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Federation of Immunological Societies\u2014Immunology Letters Short-Term Fellowship","award":["094073\/Z\/10\/Z"],"award-info":[{"award-number":["094073\/Z\/10\/Z"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Our incomplete knowledge of maternal\u2013fetal interface (MFI) physiology impedes a better understanding of the pathological mechanisms leading to pregnancy complications, such as pre-eclampsia and fetal growth restriction. At the MFI, uterine natural killer (uNK) cells do not attack fetal cells but engage in crosstalk with both fetal and maternal cells to support feto-placental development. However, mother and fetus are genetically half-mismatched and certain combinations of variable immune genes\u2014human leukocyte antigens (HLAs) and killer-cell immunoglobulin-like receptor (KIR), indeed, the most variable gene sets in the genome\u2014associate with pregnancy outcomes, suggesting that these interactions regulate uNK cell function. How do these interactions influence the physiology and pathology at the MFI? Uterine NK cell function is regulated by both maternal and fetal Major Histocompatibility Complex (MHC); however, evidence for fetal cells educating uNK cells is lacking, and new evidence shows that maternal rather than fetal MHC class I molecules educate uNK cells. Furthermore, uNK cell education works through self-recognition by the ancient and conserved NKG2A receptor. Pregnant mice lacking this receptor produce normal litter sizes, but a significant portion of the offspring have low birthweight and abnormal brain development. Evidence from a genome-wide association study of over 150,000 human pregnancies validates the finding because women whose NKG2A receptor is genetically determined to engage their own MHC class I molecules are exposed to lower risk of developing pre-eclampsia, suggesting that maternal uNK cell education is a pre-requisite for a healthy pregnancy and, likely, for healthy offspring too.<\/jats:p>","DOI":"10.3390\/ijms25168869","type":"journal-article","created":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T05:47:11Z","timestamp":1723700831000},"page":"8869","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A New Look at Immunogenetics of Pregnancy: Maternal Major Histocompatibility Complex Class I Educates Uterine Natural Killer Cells"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8636-888X","authenticated-orcid":false,"given":"Manon","family":"Bos","sequence":"first","affiliation":[{"name":"Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Colucci","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, NIHR Cambridge Biomedical Research Centre, Addenbrooke\u2019s Hospital, Cambridge CB2 0QQ, UK"},{"name":"Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1TN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0143-4004(03)00167-X","article-title":"The immunological paradox of pregnancy: A reappraisal","volume":"25","author":"Moffett","year":"2004","journal-title":"Placenta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101038","DOI":"10.1016\/j.blre.2022.101038","article-title":"Fetal and neonatal alloimmune thrombocytopenia: Current pathophysiological insights and perspectives for future diagnostics and treatment","volume":"59","author":"Stam","year":"2022","journal-title":"Blood Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1007\/s00251-017-1003-9","article-title":"The role of KIR and HLA interactions in pregnancy complications","volume":"69","author":"Colucci","year":"2017","journal-title":"Immunogenetics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/imr.12323","article-title":"Co-evolution of NK receptors and HLA ligands in humans is driven by reproduction","volume":"267","author":"Moffett","year":"2015","journal-title":"Immunol. 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