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

Gurman Kaur, Caroline B. M. Porter, Orr Ashenberg, Jack Lee, Samantha J. Riesenfeld, Matan Hofree, Maria Aggelakopoulou, Ayshwarya Subramanian, Subita Balaram Kuttikkatte, Kathrine E. Attfield, Christiane A. E. Desel, Jessica L. Davies, Hayley G. Evans, Inbal Avraham-Davidi, Lan T. Nguyen, Danielle A. Dionne, Anna E. Neumann, Lise Torp Jensen, Thomas R. Barber, Elizabeth Soilleux, Mary Carrington, Gil McVean, Orit Rozenblatt-Rosen, Aviv Regev () and Lars Fugger ()
Additional contact information
Gurman Kaur: University of Oxford
Caroline B. M. Porter: Broad Institute of MIT and Harvard
Orr Ashenberg: Broad Institute of MIT and Harvard
Jack Lee: King’s College London
Samantha J. Riesenfeld: Broad Institute of MIT and Harvard
Matan Hofree: Broad Institute of MIT and Harvard
Maria Aggelakopoulou: University of Oxford
Ayshwarya Subramanian: Broad Institute of MIT and Harvard
Subita Balaram Kuttikkatte: University of Oxford
Kathrine E. Attfield: University of Oxford
Christiane A. E. Desel: University of Oxford
Jessica L. Davies: University of Oxford
Hayley G. Evans: University of Oxford
Inbal Avraham-Davidi: Broad Institute of MIT and Harvard
Lan T. Nguyen: Broad Institute of MIT and Harvard
Danielle A. Dionne: Broad Institute of MIT and Harvard
Anna E. Neumann: Broad Institute of MIT and Harvard
Lise Torp Jensen: Aarhus University Hospital
Thomas R. Barber: University of Oxford
Elizabeth Soilleux: University of Cambridge
Mary Carrington: National Cancer Institute
Gil McVean: University of Oxford
Orit Rozenblatt-Rosen: Broad Institute of MIT and Harvard
Aviv Regev: Broad Institute of MIT and Harvard
Lars Fugger: University of Oxford

Nature Communications, 2022, vol. 13, issue 1, 1-25

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32171-w

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