Multidimensional molecular profiling reveals decidual and circulating NK cell dynamics in early and late pregnancy

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 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.