Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade

• Published in: Nature communications Vol. 13; no. 1; p. 4398
• Main Authors: Kaur, Gurman, Porter, Caroline B. M., Ashenberg, Orr, Lee, Jack, Riesenfeld, Samantha J., Hofree, Matan, Aggelakopoulou, Maria, Subramanian, Ayshwarya, Kuttikkatte, Subita Balaram, Attfield, Kathrine E., Desel, Christiane A. E., Davies, Jessica L., Evans, Hayley G., Avraham-Davidi, Inbal, Nguyen, Lan T., Dionne, Danielle A., Neumann, Anna E., Jensen, Lise Torp, Barber, Thomas R., Soilleux, Elizabeth, Carrington, Mary, McVean, Gil, Rozenblatt-Rosen, Orit, Regev, Aviv, Fugger, Lars
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/31; 14/32; 38/39; 38/77; 45; 45/91; 631/208/248; 631/250/1619/382; 631/250/2504; 64/60; 692/4017; Alleles; Animals; Biomedical engineering; Cancer; Cell Communication - genetics; Disease prevention; Female; Fetal Growth Retardation - genetics; Fetal Growth Retardation - metabolism; Fetus - metabolism; Fetuses; Genes; Haplotypes; Health risk assessment; Histocompatibility antigen HLA; HLA-C Antigens - genetics; HLA-C Antigens - metabolism; Hospitals; Humanities and Social Sciences; Immunology; Killer cell immunoglobulin-like receptors; Laboratories; Ligands; Linkage disequilibrium; Medicine; Mice; multidisciplinary; Natural killer cells; Pathogenesis; Potassium channels (inwardly-rectifying); Preeclampsia; Pregnancy; Pregnancy complications; Prevention; Science; Science (multidisciplinary); Transcriptomes; Transgenic mice; Trophoblasts - metabolism; Uterus
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32171-w

Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment. Natural Killer cells regulate foetal growth. Here the authors use a humanized transgenic mouse to demonstrate that specific HLA-C KIR2DL interactions promote changes in maternal and foetal cell transcriptomes, resulting in modifications to placental vasculature, intercellular communications and foetal growth restriction.