Single-cell immune profiling of third trimester pregnancies defines importance of chemokine receptors and prevalence of CMV-induced NK cells in the periphery and decidua

Human pregnancy presents a unique physiological state that allows for growth of an antigenically dissimilar foetus and requires specific adaptations of the immune system. The immune system plays an important role in establishing and maintaining successful pregnancy, yet deep understanding of immunological responses in pregnancy is lacking. To provide in-depth understanding of the immunological landscape of pregnancy, with a focus on NK cells, we used high-throughput cell surface proteome screening of >350 markers and scRNAseq with 130 CITE-seq antibodies to identify key differentially expressed molecules and investigated their potential roles in altered immunity. We identified skewing in NK cell subsets towards higher frequencies of CD56 ^bright cells caused by a reduced number of CD56 ^dim cells in the peripheral blood during pregnancy and provide evidence for a role of chemokine receptor, CX3CR1, in NK cell activation. In addition, we defined a new cytomegalovirus (CMV)-induced decidual NK cell population in CMV ⁺ pregnancies with tissue-residency markers. Overall, our data provide fundamental knowledge into how NK cell immunity is altered in pregnancy, and key knowledge needed to inform vaccine and therapeutic strategies to manage infections or pregnancy complications.