Parental-fetal interplay of immune genes leads to intrauterine growth restriction

G. Kaur, C.B.M. Porter, O. Ashenberg, J. Lee, S.J. Riesenfeld, M. Hofree, M. Aggelakopoulou, A. Subramanian, S.B. Kuttikkatte, K.E. Attfield, C.A.E. Desel, J.L. Davies, H.G. Evans, I.A. Davidi, L.T. Nguyen, D.A. Dionne, A.E. Neumann, L.T. Jensen, T.R. Barber, E. SoilleuxM. Carrington, G. McVean, O. Rozenblatt-Rosen, A. Regev, L. Fugger

Research output: Working paper/preprintPreprint


Intrauterine growth restriction (IUGR) of fetuses affects 5-10% of pregnancies and is associated with perinatal morbidity, mortality and long-term health issues. Understanding genetic predisposition to IUGR is challenging, owing to extensive gene polymorphisms, linkage disequilibrium, and maternal and paternal influence. Here, we demonstrate that the inhibitory receptor, KIR2DL1, expressed on maternal uterine natural killer (uNK) cells, in interaction with the paternally-inherited HLA-C∗05, an HLA-C group 2 allotype, expressed on fetal trophoblast cells, causes IUGR in a humanised mouse model. Micro-CT imaging of the uteroplacental vasculature revealed reduced uterine spiral artery diameter and increased segment length, increasing fetal blood flow resistance. Single cell RNA-Seq from the maternal-fetal interface highlighted expression programs activated by KIR2DL1-induced IUGR in several placental cell types, including degradation of extracellular matrix components, angiogenesis, and uNK cell communication, suggesting a complex response underlying IUGR. As current IUGR treatments are insufficient, our findings provide important insight for drug development. The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Original languageEnglish
StatePublished - 2021

Publication series

ISSN (Print)2692-8205

Bibliographical note

Export Date: 27 November 2022

Correspondence Address: Fugger, L.; Mrc Human Immunology Unit, United Kingdom; email:

Correspondence Address: Regev, A.; Broad Institute of Mit and Harvard, United States; email:


  • immunology


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