Advisor(s)
Laurie Harrington
Committee Member(s)
Alecia Gross
Holly Richter
James George
Scott Gordon
School
College of Arts and Sciences
Document Type
Dissertation
Department (new version)
Biology
Date of Award
9-11-2025
Abstract
Uterine natural killer (uNK) cells are specialized tissue-resident lymphocytes that are essential for successful pregnancy, yet the molecular pathways governing their development remain poorly defined. This knowledge gap hinders our ability to understand and treat immunological complications of pregnancy, such as recurrent pregnancy loss and pre-eclampsia. This dissertation addresses the fundamental question of how human uNK cells arise and differentiate, first within the non-pregnant endometrium and subsequently within the decidua of early pregnancy. Using single-cell RNA sequencing of matched human blood and endometrial samples, we first delineate the developmental trajectory of endometrial NK (eNK) cells. We demonstrate that eNK cells differentiate from circulating peripheral blood precursors through a series of developmental intermediates. This process is driven by a novel, core transcriptional program we term the Early Residency Program (ERP), which is initiated upon tissue entry under the influence of the endometrial microenvironment and is required for the maturation of eNK cells into decidual-like states prior to pregnancy. We then investigate how this foundational program is utilized during the transition to pregnancy by integrating endometrial and decidual single-cell datasets. This work reveals that the diverse landscape of first-trimester decidual NK (dNK) cells arises from the continued maturation of their eNK precursors. Crucially, we find that the ERP is not a monolithic program but is partitioned into two distinct, functionally coherent modules. The divergent expression of these modules—ERP1 and ERP2—is the primary driver of dNK cell heterogeneity, orchestrating the differentiation of transitional cells into the canonical dNK1 and dNK3 subsets. Collectively, this dissertation establishes a new paradigm for human uNK cell development, redefining it as a continuous differentiation trajectory governed by the modlar expression of a core residency program. By uncovering the ERP and its modular logic, we provide a new molecular framework for understanding the origins of dNK cell diversity and offer novel avenues for investigating the immunological basis of reproductive health and disease.
ProQuest ID
Recommended Citation
Greene, Morgan Elizabeth-Carolyn, "Origin And Differentiation Of Uterine Natural Killer Cells" (2025). All ETDs from UAB. 7435.
https://digitalcommons.library.uab.edu/etd-collection/7435
