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

Successful pregnancy requires a well-coordinated adaptation of the immune system. To understand the immunological landscape in pregnancy, we performed a multiplexed cell-surface proteome screen of >350 markers on NK cells, CD4+, CD8+ and γδ T cells, B cells and monocytes in pregnant peripheral blood, cord blood and decidua, and scRNAseq, including 130 CITE-seq antibodies, on NK cells from the blood and decidua. In pregnancy, NK cells had increased AREG, SOCS1, HLA-D family gene expression, and increased CCR5 and HLA-DR, and decreased CD9, CD36, and CX3CR1 at the protein level. Pregnancy caused a shift toward higher frequencies of CD56bright cells in the blood caused by a numerical reduction in CD56dim cells. We demonstrate a role for chemokine receptor CX3CR1 in NK cell activation and define a subset of cytomegalovirus-induced decidual NK cells. Overall, this study provides key insights on NK cell immunity in pregnancy and reveals fundamental differences in the NK cell compartment during gestation. Taken together, this information will help improve treatments and immunotherapy strategies in pregnant individuals.