Human CD56CD39 DNK Cells Support Fetal Survival Through Controlling Trophoblastic Cell Fate: Immune Mechanisms of Recurrent Early Pregnancy Loss

Overview

Journal Natl Sci Rev

Date 2024 Jul 5

PMID 38966071

Authors

Wentong Jia

Liyang Ma

Xin Yu

Feiyang Wang

Qian Yang

Xiaoye Wang

Mengjie Fan

Yan Gu

Ran Meng

Jian Wang

Yuxia Li

Rong Li

Xuan Shao

Yan-Ling Wang

Affiliations

Soon will be listed here.

Abstract

Decidual natural killer (dNK) cells are the most abundant immune cells at the maternal-fetal interface during early pregnancy in both mice and humans, and emerging single-cell transcriptomic studies have uncovered various human dNK subsets that are disrupted in patients experiencing recurrent early pregnancy loss (RPL) at early gestational stage, suggesting a connection between abnormal proportions or characteristics of dNK subsets and RPL pathogenesis. However, the functional mechanisms underlying this association remain unclear. Here, we established a mouse model by adoptively transferring human dNK cells into pregnant NOG (NOD/Shi-/IL-2Rγ) mice, where human dNK cells predominantly homed into the uteri of recipients. Using this model, we observed a strong correlation between the properties of human dNK cells and pregnancy outcome. The transfer of dNK cells from RPL patients (dNK-RPL) remarkably worsened early pregnancy loss and impaired placental trophoblast cell differentiation in the recipients. These adverse effects were effectively reversed by transferring CD56CD39 dNK cells. Mechanistic studies revealed that CD56CD39 dNK subset facilitates early differentiation of mouse trophoblast stem cells (mTSCs) towards both invasive and syncytial pathways through secreting macrophage colony-stimulating factor (M-CSF). Administration of recombinant M-CSF to NOG mice transferred with dNK-RPL efficiently rescued the exacerbated pregnancy outcomes and fetal/placental development. Collectively, this study established a novel humanized mouse model featuring functional human dNK cells homing into the uteri of recipients and uncovered the pivotal role of M-CSF in fetal-supporting function of CD56CD39 dNK cells during early pregnancy, highlighting that M-CSF may be a previously unappreciated therapeutic target for intervening RPL.

Citing Articles

Hypoxia-Induced O-GlcNAcylation of GATA3 Leads to Excessive Testosterone Production in Preeclamptic Placentas.

Liu J, Yang Y, Wu H, Dang F, Yu X, Wang F MedComm (2020). 2025; 6(3):e70115.

PMID: 39991625 PMC: 11847629. DOI: 10.1002/mco2.70115.

References

Yamada D, Iyoda T, Vizcardo R, Shimizu K, Sato Y, Endo T . Efficient Regeneration of Human Vα24 Invariant Natural Killer T Cells and Their Anti-Tumor Activity In Vivo. Stem Cells. 2016; 34(12):2852-2860. DOI: 10.1002/stem.2465. View

Yadi H, Burke S, Madeja Z, Hemberger M, Moffett A, Colucci F . Unique receptor repertoire in mouse uterine NK cells. J Immunol. 2008; 181(9):6140-7. DOI: 10.4049/jimmunol.181.9.6140. View

Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K . NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002; 100(9):3175-82. DOI: 10.1182/blood-2001-12-0207. View

Ji L, Brkic J, Liu M, Fu G, Peng C, Wang Y . Placental trophoblast cell differentiation: physiological regulation and pathological relevance to preeclampsia. Mol Aspects Med. 2013; 34(5):981-1023. DOI: 10.1016/j.mam.2012.12.008. View

Ito R, Takahashi T, Ito M . Humanized mouse models: Application to human diseases. J Cell Physiol. 2017; 233(5):3723-3728. DOI: 10.1002/jcp.26045. View

Jokhi P, King A, Boocock C, Loke Y . Secretion of colony stimulating factor-1 by human first trimester placental and decidual cell populations and the effect of this cytokine on trophoblast thymidine uptake in vitro. Hum Reprod. 1995; 10(10):2800-7. DOI: 10.1093/oxfordjournals.humrep.a135794. View

Schlums H, Cichocki F, Tesi B, Theorell J, Beziat V, Holmes T . Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity. 2015; 42(3):443-56. PMC: 4612277. DOI: 10.1016/j.immuni.2015.02.008. View

Allen T, Brehm M, Bridges S, Ferguson S, Kumar P, Mirochnitchenko O . Humanized immune system mouse models: progress, challenges and opportunities. Nat Immunol. 2019; 20(7):770-774. PMC: 7265413. DOI: 10.1038/s41590-019-0416-z. View

Erlebacher A . Immunology of the maternal-fetal interface. Annu Rev Immunol. 2013; 31:387-411. DOI: 10.1146/annurev-immunol-032712-100003. View

10.

Rosen D, Bettadapura J, Alsharifi M, Mathew P, Warren H, Lanier L . Cutting edge: lectin-like transcript-1 is a ligand for the inhibitory human NKR-P1A receptor. J Immunol. 2005; 175(12):7796-9. DOI: 10.4049/jimmunol.175.12.7796. View

11.

Saito S, Saito M, Enomoto M, Ito A, Motoyoshi K, Nakagawa T . Human macrophage colony-stimulating factor induces the differentiation of trophoblast. Growth Factors. 1993; 9(1):11-9. DOI: 10.3109/08977199308991578. View

12.

Faulk W, Temple A . Distribution of beta2 microglobulin and HLA in chorionic villi of human placentae. Nature. 1976; 262(5571):799-802. DOI: 10.1038/262799a0. View

13.

Ratsep M, Felker A, Kay V, Tolusso L, Hofmann A, Croy B . Uterine natural killer cells: supervisors of vasculature construction in early decidua basalis. Reproduction. 2014; 149(2):R91-102. DOI: 10.1530/REP-14-0271. View

14.

Aldemir H, Prodhomme V, Dumaurier M, Retiere C, Poupon G, Cazareth J . Cutting edge: lectin-like transcript 1 is a ligand for the CD161 receptor. J Immunol. 2005; 175(12):7791-5. DOI: 10.4049/jimmunol.175.12.7791. View

15.

Vento-Tormo R, Efremova M, Botting R, Turco M, Vento-Tormo M, Meyer K . Single-cell reconstruction of the early maternal-fetal interface in humans. Nature. 2018; 563(7731):347-353. PMC: 7612850. DOI: 10.1038/s41586-018-0698-6. View

16.

Pollard J, Hunt J, Wiktor-Jedrzejczak W, Stanley E . A pregnancy defect in the osteopetrotic (op/op) mouse demonstrates the requirement for CSF-1 in female fertility. Dev Biol. 1991; 148(1):273-83. DOI: 10.1016/0012-1606(91)90336-2. View

17.

Pampfer S, Daiter E, Barad D, Pollard J . Expression of the colony-stimulating factor-1 receptor (c-fms proto-oncogene product) in the human uterus and placenta. Biol Reprod. 1992; 46(1):48-57. DOI: 10.1095/biolreprod46.1.48. View

18.

. Natural killer cells and pregnancy. Nat Rev Immunol. 2002; 2(9):656-63. DOI: 10.1038/nri886. View

19.

Zeltser L, Leibel R . Roles of the placenta in fetal brain development. Proc Natl Acad Sci U S A. 2011; 108(38):15667-8. PMC: 3179106. DOI: 10.1073/pnas.1112239108. View

20.

Xiong S, Sharkey A, Kennedy P, Gardner L, Farrell L, Chazara O . Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation. J Clin Invest. 2013; 123(10):4264-72. PMC: 4382274. DOI: 10.1172/JCI68991. View