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; Lars Fugger

doi:10.1038/s41467-022-32171-w

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

Nat Commun. 2022 Jul 29;13(1):4398. doi: 10.1038/s41467-022-32171-w.

Authors

Gurman Kaur^#^{1

2}, Caroline B M Porter^#², Orr Ashenberg², Jack Lee³, Samantha J Riesenfeld^{2

4

5}, Matan Hofree², Maria Aggelakopoulou⁶, Ayshwarya Subramanian², Subita Balaram Kuttikkatte¹, Kathrine E Attfield⁶, Christiane A E Desel^{6

7}, Jessica L Davies⁶, Hayley G Evans⁶, Inbal Avraham-Davidi², Lan T Nguyen², Danielle A Dionne², Anna E Neumann⁸, Lise Torp Jensen⁹, Thomas R Barber¹, Elizabeth Soilleux¹⁰, Mary Carrington^{11

12}, Gil McVean¹³, Orit Rozenblatt-Rosen^{2

14}, Aviv Regev^{15

16

17

18}, Lars Fugger^{19

20

21}

Affiliations

¹ MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
² Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Department of Biomedical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK.
⁴ Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.
⁵ Department of Medicine, University of Chicago, Chicago, IL, USA.
⁶ Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
⁷ University Department of Neurology, University Hospital Magdeburg, Magdeburg, Germany.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹ Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
¹⁰ Department of Pathology, Tennis Court Rd, University of Cambridge, Cambridge, England.
¹¹ Basic Science Program, Frederick National Laboratory for Cancer Research in the Laboratory of Integrative Cancer Immunology, National Cancer Institute, Bethesda, MD, USA.
¹² Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
¹³ Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
¹⁴ Genentech, 1 DNA Way, South San Francisco, CA, USA.
¹⁵ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aregev@broadinstitute.org.
¹⁶ Massachusetts Institute of Technology, Department of Biology, Cambridge, MA, USA. aregev@broadinstitute.org.
¹⁷ Howard Hughes Medical Institute, Chevy Chase, MD, USA. aregev@broadinstitute.org.
¹⁸ Genentech, 1 DNA Way, South San Francisco, CA, USA. aregev@broadinstitute.org.
¹⁹ MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. lars.fugger@ndcn.ox.ac.uk.
²⁰ Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. lars.fugger@ndcn.ox.ac.uk.
²¹ Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark. lars.fugger@ndcn.ox.ac.uk.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Communication / genetics
Female
Fetal Growth Retardation* / genetics
Fetal Growth Retardation* / metabolism
Fetus / metabolism
HLA-C Antigens / genetics
HLA-C Antigens / metabolism
Mice
Pregnancy
Trophoblasts* / metabolism

Substances

HLA-C Antigens

Abstract

Publication types

MeSH terms

Substances

Grants and funding