Mechanisms of aberrant tissue residency programming of uterine natural killer cells in uterus transplantation

Abstract Uterine natural killer cells (uNK) are the most common human decidual lymphocytes, but origin and ontogeny of uNKs remain unclear. Studies uterus transplant recipients (UTx) suggest that originate in blood, how these become tissue resident differentiate into NK is unknown. We studied molecular mechanisms governing uNK residency endometrium using single-cell RNA-seq flow cytometry analyses. trNK with a CD49a+ CD16− phenotype were abundant CD56+ 5 healthy control volunteers (HCs) [27±17% vs. 4±2.7% CD49a− CD16+ conventional (cNK); p<0.02]. differentially expressed genes associated T cell residency, such as ITGAE ZNF683, compared to cNK. Although peripheral blood can express CD103 when incubated TGF-β, trNKs upregulated expression response IL-15 alone vitro. Given dependency on NFAT signals, we by incubating (n=7) calcineurin inhibitor FK506, which decreased IL-15-induced upregulation (81% CD103+ [IL-15 alone] 70% CD103− + FK506]; p=0.02). next tested vivo relevance findings comparing frequency endometrial biopsies five HCs two one UTx FK506 immunosuppression. The recipient had significantly fewer among CD45+ (HC: 27±17% UTx: 4.3±2%; p=0.04). Altogether calcium signals influence significant implications for recipients. This work was supported from UAB AMC21 support program University Alabama at Birmingham. P. Porrett additionally NIH R01 AI145905.