Multidimensional molecular profiling reveals decidual and circulating NK cell dynamics in early and late pregnancy
- Author(s)
- Habel, JR; Nguyen, THO; Allen, LF; Skinner, MJ; Kedzierski, L; Allen, EK; Li, S; de Alwis, N; Hagen, RR; Doggett, K; Jia, X; Tarasova, I; Minervina, AA; Pogorelyy, MV; Holloway, AI; Mathew, NL; Saunders, PM; Clatch, A; Evrard, M; Xu, C; Koay, HF; Abdullah-Al-Kamran Khan, M; Mackay, LK; Barrow, AD; Douros, C; Karapanagiotidis, T; Nicholson, S; Bond, K; Williamson, DA; Hui, L; Lappas, M; Walker, S; Nicholson, SE; Hannan, NJ; Brooks, AG; Schroeder, J; Crawford, JC; Thomas, PG; Rowntree, LC; Kedzierska, K;
- Journal Title
- EBioMedicine
- Abstract
- BACKGROUND: Human pregnancy presents a unique physiological state that allows for growth of an antigenically dissimilar foetus. The immune system plays a key role in establishing and maintaining successful pregnancy, yet detailed understanding of immunological responses in pregnancy is lacking. METHODS: We defined the immunological landscape in pregnancy by screening >350 markers on NK cells, CD4(+), CD8(+) and γδ T cells, B cells and monocytes in third-trimester pregnancy peripheral blood, cord blood and decidua, and by performing single-cell RNA sequencing (scRNAseq), including 130 CITE-seq antibodies, on NK cells from the blood and decidua of third-trimester pregnancies. We validated our findings in additional blood and decidua samples from first- and third-trimester pregnancies. Blood samples from non-pregnant women were used as a control group for comparison. FINDINGS: Our multiomic approaches revealed altered surface proteomes in lymphoid and myeloid immune subsets during third-trimester pregnancy, in comparison to non-pregnant women. In the blood during pregnancy, circulating NK cells displayed increased SOCS1 (FDR < 0.001) and AREG (FDR < 0.001), both involved in tightly regulating immune responses, as well as HLA-D family (FDR < 0.05-0.0001) gene expression, with increased CCR5 (p < 0.01-0.001) and HLA-DR (p < 0.01-0.001), and decreased CD9 (p < 0.001), CD36 (p < 0.05-0.001), and CX3CR1 (p < 0.05) at the protein level, validated in samples from first- and third-trimester pregnancies. Our analysis of decidual NK (dNK) cells demonstrated a decline in the dNK1 subset between first-trimester decidua and third-trimester decidua basalis (p < 0.0001) and parietalis (p < 0.01), and identified an adaptive-like subset with high expression of cytotoxic molecules, which could be distinguished from the previously described dNK1-3 subsets and was enriched in decidua from women with a history of cytomegalovirus infection (p < 0.05). Functionally, we observed enhanced control of IFN-γ secretion in response to proinflammatory IL-12/IL-18 cytokines in pregnancy (p < 0.05-0.01), however induction of SOCS1 protein expression remained similar between pregnant and non-pregnant women. INTERPRETATION: Overall, our study provides key insights into immunity in pregnancy and reveals fundamental differences in the NK cell compartment. Understanding pregnancy-specific immunology fills important knowledge gaps to better inform the rational design of vaccines, immunotherapies and identification of biomarkers for safe pregnancy outcomes. FUNDING: Australian National Health and Medical Research Council, Australian Medical Research Future Fund, and the National Institute of Allergy and Infectious Diseases.
- Publisher
- Elsevier
- Keywords
- Cytomegalovirus; Decidua; Multiomics; NK cells; Pregnancy
- Research Division(s)
- Inflammation
- PubMed ID
- 42822323
- Publisher's Version
- https://doi.org/10.1016/j.ebiom.2026.106495
- Open Access at Publisher's Site
https://doi.org/10.1016/j.ebiom.2026.106495- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-10-12 01:25:22
Last Modified: 2026-10-12 01:25:31