The fetal trophoblast cell marker HLA-G activates a type I interferon response in primary NK cells through the receptor KIR2DL4

Most of the lymphocytes in the human pregnant uterus are natural killer (NK) cells. Here, we showed that soluble HLA-G expressed by fetal trophoblast cells at the maternal-fetal interface in early pregnancy stimulated transcription of mostly the same genes in primary NK cells as an agonistic antibody to the receptor KIR2DL4. An exception was the transcription of type I interferon (IFN-I)-stimulated genes (ISGs), which were selectively induced by HLA-G through a noncanonical pathway. This ISG response required the transcription factor IRF7 and the kinase JAK1. The carboxyl-terminal portion of the KIR2DL4 cytoplasmic tail includes a sequence analogous to conserved JAK1 binding sites in IFN receptors and was required for JAK1 binding to KIR2DL4. Phosphorylation of IRF7 and the JAK substrate STAT2, which link IFN-I stimulation to ISG transcription, was detected in the nuclei of HLA-G-stimulated NK cells. Single-cell RNA sequencing (scRNA-seq) showed that HLA-G induced a broader transcriptional response in CD56^bright NK cells than in CD56^dim NK cells and that ISG expression was similar in both NK cell subsets. Comparison of our data with scRNA-seq data from the early maternal-fetal interface revealed that HLA-G induced the transcription of genes that distinguish decidual NK cells from maternal blood NK cells. Thus, ISG transcription, which is inducible by HLA-G, is detected in early pregnancy and may underlie intrinsic antipathogen resistance of NK cells in the maternal decidua.