Early residency program defines tissue-resident NK cell differentiation in human endometrium 4533

Abstract Description Uterine tissue-resident natural killer (trNK) cells are essential for pregnancy, supporting spiral artery remodeling and fetal growth. Although mouse studies suggest trNK cells arise from both resident and recruited populations, the molecular programming governing human trNK residency remains poorly understood. This study aimed to elucidate the molecular programming of trNK cells as they enter the uterus. Using multiomic analyses, we compared NK cells from human endometrium and peripheral blood, identifying a conserved early residency program (ERP) originally characterized in CD8 T resident memory cells. The ERP comprises 80 genes, including transcription factors FOS, JUNB, NR4A2, and EGR1, previously shown to be critical for tissue residency. ERP enrichment was observed in ITGA1lo endometrial NK cells, termed founder NK (fNK) cells, due to their transcriptional similarity to peripheral blood NCAM1hi cells despite their endometrial origin. From fNK cells to mature ITGA1+ trNK populations, ERP expression progressively increased. Transcriptomic and proteomic analyses revealed differential ERP utilization among trNK subsets. A foundational ERP, including NR4A2, EGR1, and FOS, associated with trNK1 cells, while a divergent ERP, comprising JUNB and JUND, was enriched in trNK3 cells. These findings demonstrate that early transcriptional regulation drives residency establishment and shapes mature functional specialization, advancing our understanding of residency molecular drivers. Funding Sources Supported by NIH/NICHD 1F31HD114429 Topic Categories Mucosal and Regional Immunology (MUC)