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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 4398 |
| Tidsskrift | Nature Communications |
| Vol/bind | 13 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:L.F. was supported by the Wellcome Trust (grant no. 100308/Z/12/Z), Danish National Research Foundation, Takeda, the Medical Research Council (grant no. MC_UU_12010/3), the Oak Foundation (grant no. OCAY-15-520) and the NIHR Oxford BRC. G.M. was supported by the Wellcome Trust (grant no. 100956/Z/13/Z) and the Li Ka Shing Foundation. A.R. was an Investigator of the Howard Hughes Medical Institute. This project was also funded in part by the Klarman Cell Observatory. O.A. was supported by the NIDDK (5RC2DK116691). This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. We would like to thank V. Sexl (University of Veterinary Medicine of Vienna) for the NCR1-iCre transgenic mice, P. Höglund (Karolinska Institutet) for H2-Kb H2-Db knockout mice, B. Davies (Wellcome Trust Centre for Human Genetics, University of Oxford) for transgenic mouse generation services, D. Bowman, A. Ortiz, and S. Jerman (Indica Labs, Albuquerque, NM, USA) for RNAscope image analysis services, L. Gaffney for figure edits, G. Holländer and M. Deadman (Dept. of Pediatrics, University of Oxford) for help with TEC isolations, C. Smillie, S. Simmons, A. Haber (Broad Institute of MIT and Harvard), and A.-C.Villani (Harvard Medical School) for brainstorming and discussions, G. Douglas and V. Rashbrook (Radcliffe Dept. of Medicine, University of Oxford) for help with blood pressure measurement in mice, A. Vernet (University of Oxford) for helping with micro-CT scanning, R. Kuehn (Helmholtz Center Munich) for help with transgenic vector design. We also thank the MRC WIMM core Transgenic service team for providing cryopreservation services. We would like to acknowledge S.-A. Clark, C. Waugh, K. Clark, and P. Sopp in the flow cytometry facility at the MRC WIMM for providing cell sorting services. The flow cytometry facility is supported by the MRC HIU; MRC MHU (MC_UU_12009); NIHR Oxford BRC; Kay Kendall Leukaemia Fund (KKL1057), John Fell Fund (131/030 and 101/517), the EPA fund (CF182 and CF170) and by the MRC WIMM Strategic Alliance awards G0902418 and MC_UU_12025.
Funding Information:
L.F. was supported by the Wellcome Trust (grant no. 100308/Z/12/Z), Danish National Research Foundation, Takeda, the Medical Research Council (grant no. MC_UU_12010/3), the Oak Foundation (grant no. OCAY-15-520) and the NIHR Oxford BRC. G.M. was supported by the Wellcome Trust (grant no. 100956/Z/13/Z) and the Li Ka Shing Foundation. A.R. was an Investigator of the Howard Hughes Medical Institute. This project was also funded in part by the Klarman Cell Observatory. O.A. was supported by the NIDDK (5RC2DK116691). This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. We would like to thank V. Sexl (University of Veterinary Medicine of Vienna) for the NCR1-iCre transgenic mice, P. Höglund (Karolinska Institutet) for H2-Kb H2-Db knockout mice, B. Davies (Wellcome Trust Centre for Human Genetics, University of Oxford) for transgenic mouse generation services, D. Bowman, A. Ortiz, and S. Jerman (Indica Labs, Albuquerque, NM, USA) for RNAscope image analysis services, L. Gaffney for figure edits, G. Holländer and M. Deadman (Dept. of Pediatrics, University of Oxford) for help with TEC isolations, C. Smillie, S. Simmons, A. Haber (Broad Institute of MIT and Harvard), and A.-C.Villani (Harvard Medical School) for brainstorming and discussions, G. Douglas and V. Rashbrook (Radcliffe Dept. of Medicine, University of Oxford) for help with blood pressure measurement in mice, A. Vernet (University of Oxford) for helping with micro-CT scanning, R. Kuehn (Helmholtz Center Munich) for help with transgenic vector design. We also thank the MRC WIMM core Transgenic service team for providing cryopreservation services. We would like to acknowledge S.-A. Clark, C. Waugh, K. Clark, and P. Sopp in the flow cytometry facility at the MRC WIMM for providing cell sorting services. The flow cytometry facility is supported by the MRC HIU; MRC MHU (MC_UU_12009); NIHR Oxford BRC; Kay Kendall Leukaemia Fund (KKL1057), John Fell Fund (131/030 and 101/517), the EPA fund (CF182 and CF170) and by the MRC WIMM Strategic Alliance awards G0902418 and MC_UU_12025.
Publisher Copyright:
© 2022, The Author(s).