Tissue-resident NK cell development and function in pregnancy and transplantation: lessons learned from human uterus transplant recipients

The overarching goal of this project is to improve our mechanistic understanding of pregnancy complications in organ transplant recipients. By studying a patient population with increased risks of pre-eclampsia and fetal growth restriction, this project fills critical knowledge gaps in reproductive immunology and improves the health of all women. Pregnancy in organ transplant recipients has historically been difficult to study because reproductive age females represent a minority of transplant recipients and pregnancy has been discouraged given concerns around maternal and fetal health. We overcome these prior limitations by leveraging our access to a unique cohort of transplant recipients who receive a uterus transplant for the express purpose of gestation and delivery. Notably, uterus transplant recipients have high rates of pre-eclampsia and other disorders of placentation, which may be due to perturbations in natural killer cell biology as these cells play critical roles in spiral artery remodeling and placentation. Hence, defects in uNK development, homeostasis, and function likely contribute to the pathogenesis of pregnancy complications. Importantly, our prior studies suggest that immunosuppression medications that transplant recipients receive may impact the survival, localization, and function of uterine natural killer cells, thereby providing mechanistic insights into why pregnancy complications in organ transplant recipients are frequent. Notably, the alterations we have observed in uterine NK cells in uterus transplant recipients associate with abnormal placental histology and have had clinical consequences. In this proposal, we thus build upon these findings to better understand the molecular mechanisms underpinning defects in uNK development, homeostasis and function using uterus transplantation as a model system. We accomplish these goals by analyzing endometrial biopsies from uterus transplant recipients as well as healthy controls using state-of-the- art single-cell technologies (i.e., single cell RNA-sequencing, single-nuclear RNA-seq; CITE-seq) alongside high dimensional, multi-parameter flow cytometry and imaging studies (i.e., immunofluorescence microscopy and spatial transcriptomics). These experiments using human samples are complemented by in vivo mouse studies where placentation in the setting of immunosuppression can be better studied across all phases of pregnancy.