TGFb1 Suppresses the Activation of Distinct DNK Subpopulations in Preeclampsia

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2018 Dec 24

PMID 30579870

Citations 41

Authors

Jianhong Zhang

Caroline E Dunk

Oksana Shynlova

Isabella Caniggia

Stephen J Lye

Affiliations

Soon will be listed here.

Abstract

Background: Decidual natural killer (dNK) cells are the predominant lymphocytes accumulated at the maternal-fetal interface. Regulatory mechanism of dNK cells in preeclampsia, a gestational complication characterized by high blood pressure and increased proteinuria occurring after 20 weeks pregnancy, is not completely understood.

Methods: Multi-parameter flow cytometry is applied to investigate the phenotype and function of dNK cells freshly isolated from decidual samples or conditionally cultured by TGFb stimulation.

Findings: In preeclampsia, we documented elevated numbers of CD56 CD3 dNK cells in close proximity to Foxp3 regulatory T (Treg) cells within the decidua. In vitro experiments using dNK cells from early gestation showed that dNK activation (IFNG, IL-8 and CD107a) can be downregulated by Treg cells. The expression of these markers by dNK cells was significantly lower in preeclampsia. We also observed a positive correlation between the expression of dNK activation receptors (NKp30 and NKG2D) and the expression of IFNG in specific dNK subsets. TGFb levels are increased in the decidua of preeclamptic pregnancies. We analyzed co-expression of activation (IFNG/IL-8/CD107a) and angiogenic (VEGF) markers in dNK cells. TGFb treatment reduced while blockade of TGFb increased co-expression of these markers.

Interpretation: Our findings suggest that elevated decidual TGFb1 supresses the activation of specific subsets of dNK which in turn contributes to the uteroplacental pathology associated with the onset of preeclampsia.

Citing Articles

Enhanced myofibroblast differentiation of eMSCs in intrauterine adhesions.

Song J, Li M, Tao Y, Li Y, Mai C, Zhang J Stem Cell Res Ther. 2025; 16(1):35.

PMID: 39901307 PMC: 11792338. DOI: 10.1186/s13287-025-04183-y.

Trained innate immunity as a potential link between preeclampsia and future cardiovascular disease.

Carrasco-Wong I, Sanchez J, Gutierrez J, Chiarello D Front Endocrinol (Lausanne). 2025; 15:1500772.

PMID: 39741876 PMC: 11685753. DOI: 10.3389/fendo.2024.1500772.

Maternal Soluble Programmed Death Ligand-1 (sPD-L1) and T-regulatory Cells (Tregs) Alteration in Preeclampsia: A Cross-Sectional Study From Eastern India.

Dash P, Nayak S, Koppisetty B Cureus. 2024; 16(8):e67877.

PMID: 39328700 PMC: 11426926. DOI: 10.7759/cureus.67877.

Behind the Curtain of Abnormal Placentation in Pre-Eclampsia: From Molecular Mechanisms to Histological Hallmarks.

Gusella A, Martignoni G, Giacometti C Int J Mol Sci. 2024; 25(14).

PMID: 39063129 PMC: 11277090. DOI: 10.3390/ijms25147886.

The landscape of -methyladenosine (mA) modification in mRNA of the decidua in severe preeclampsia.

Tong J, Li H, Zhang L, Zhang C Biomol Biomed. 2024; 24(6):1827-1847.

PMID: 38958464 PMC: 11496874. DOI: 10.17305/bb.2024.10532.

References

Caniggia I, Kuliszewsky M, Post M, Lye S . Inhibition of TGF-beta 3 restores the invasive capability of extravillous trophoblasts in preeclamptic pregnancies. J Clin Invest. 1999; 103(12):1641-50. PMC: 408387. DOI: 10.1172/JCI6380. View

Koopman L, Kopcow H, Rybalov B, Boyson J, Orange J, Schatz F . Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med. 2003; 198(8):1201-12. PMC: 2194228. DOI: 10.1084/jem.20030305. View

Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim Y . Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006; 12(6):642-9. DOI: 10.1038/nm1429. View

Sasaki Y, Darmochwal-Kolarz D, Suzuki D, Sakai M, Ito M, Shima T . Proportion of peripheral blood and decidual CD4(+) CD25(bright) regulatory T cells in pre-eclampsia. Clin Exp Immunol. 2007; 149(1):139-45. PMC: 1942015. DOI: 10.1111/j.1365-2249.2007.03397.x. View

Williams P, Bulmer J, Searle R, Innes B, Robson S . Altered decidual leucocyte populations in the placental bed in pre-eclampsia and foetal growth restriction: a comparison with late normal pregnancy. Reproduction. 2009; 138(1):177-84. DOI: 10.1530/REP-09-0007. View

Redman C, Sargent I . Immunology of pre-eclampsia. Am J Reprod Immunol. 2010; 63(6):534-43. DOI: 10.1111/j.1600-0897.2010.00831.x. View

Allan D, Rybalov B, Awong G, Zuniga-Pflucker J, Kopcow H, Carlyle J . TGF-β affects development and differentiation of human natural killer cell subsets. Eur J Immunol. 2010; 40(8):2289-95. PMC: 3066635. DOI: 10.1002/eji.200939910. View

Toldi G, Saito S, Shima T, Halmos A, Veresh Z, Vasarhelyi B . The frequency of peripheral blood CD4+ CD25high FoxP3+ and CD4+ CD25- FoxP3+ regulatory T cells in normal pregnancy and pre-eclampsia. Am J Reprod Immunol. 2012; 68(2):175-80. DOI: 10.1111/j.1600-0897.2012.01145.x. View

Marcoe J, Lim J, Schaubert K, Fodil-Cornu N, Matka M, McCubbrey A . TGF-β is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy. Nat Immunol. 2012; 13(9):843-50. PMC: 3426626. DOI: 10.1038/ni.2388. View

10.

Hsu P, Santner-Nanan B, Dahlstrom J, Fadia M, Chandra A, Peek M . Altered decidual DC-SIGN+ antigen-presenting cells and impaired regulatory T-cell induction in preeclampsia. Am J Pathol. 2012; 181(6):2149-60. DOI: 10.1016/j.ajpath.2012.08.032. View

11.

Cerdeira A, Rajakumar A, Royle C, Lo A, Husain Z, Thadhani R . Conversion of peripheral blood NK cells to a decidual NK-like phenotype by a cocktail of defined factors. J Immunol. 2013; 190(8):3939-48. PMC: 3742368. DOI: 10.4049/jimmunol.1202582. View

12.

Zhang J, Dunk C, Lye S . Sphingosine signalling regulates decidual NK cell angiogenic phenotype and trophoblast migration. Hum Reprod. 2013; 28(11):3026-37. DOI: 10.1093/humrep/det339. View

13.

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

14.

Bartmann C, Segerer S, Rieger L, Kapp M, Sutterlin M, Kammerer U . Quantification of the predominant immune cell populations in decidua throughout human pregnancy. Am J Reprod Immunol. 2013; 71(2):109-19. DOI: 10.1111/aji.12185. View

15.

Wallace A, Fraser R, Gurung S, Goulwara S, Whitley G, Johnstone A . Increased angiogenic factor secretion by decidual natural killer cells from pregnancies with high uterine artery resistance alters trophoblast function. Hum Reprod. 2014; 29(4):652-60. PMC: 3949498. DOI: 10.1093/humrep/deu017. View

16.

Kieckbusch J, Gaynor L, Moffett A, Colucci F . MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodelling. Nat Commun. 2014; 5:3359. PMC: 3948146. DOI: 10.1038/ncomms4359. View

17.

Moffett A, Colucci F . Uterine NK cells: active regulators at the maternal-fetal interface. J Clin Invest. 2014; 124(5):1872-9. PMC: 4001528. DOI: 10.1172/JCI68107. View

18.

Jiang T, Chaturvedi V, Ertelt J, Kinder J, Clark D, Valent A . Regulatory T cells: new keys for further unlocking the enigma of fetal tolerance and pregnancy complications. J Immunol. 2014; 192(11):4949-56. PMC: 4030688. DOI: 10.4049/jimmunol.1400498. View

19.

Chaiworapongsa T, Chaemsaithong P, Yeo L, Romero R . Pre-eclampsia part 1: current understanding of its pathophysiology. Nat Rev Nephrol. 2014; 10(8):466-80. PMC: 5893150. DOI: 10.1038/nrneph.2014.102. View

20.

Wallace A, Whitley G, Thilaganathan B, Cartwright J . Decidual natural killer cell receptor expression is altered in pregnancies with impaired vascular remodeling and a higher risk of pre-eclampsia. J Leukoc Biol. 2014; 97(1):79-86. PMC: 4377829. DOI: 10.1189/jlb.2A0614-282R. View