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 SoilleuxMary Carrington, Gil McVean, Orit Rozenblatt-Rosen, Aviv Regev*, Lars Fugger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageAmerican English
Article number4398
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

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