TGF-β drives the conversion of conventional NK cells into uterine tissue-resident NK cells to support murine pregnancy

Abstract Tissue microenvironments shape lymphocyte differentiation to align immune function with local physiological demands. Uterine natural killer cells are critical for reproductive success, yet the molecular cues in the uterus that instruct their specialized identities remain incompletely understood. Here, we identify a TGF-β–dependent differentiation pathway by which circulating conventional NK cells convert into uterine tissue-resident NK cells during murine pregnancy. Loss of TGF-β receptor II expression in Ncr1-expressing cells disrupted this conversion, markedly reducing tissue-resident NK cells in the gravid uterus. Impaired TGF-β–driven uterine tissue-resident NK cell differentiation during murine pregnancy led to abnormal spiral artery remodeling and increased fetal resorption rates at midgestation, ultimately reducing litter sizes at birth. Collectively, these findings define TGF-β as a pivotal driver of tissue-resident NK cell differentiation in the gravid uterus and establish a mechanistic framework through which the uterine microenvironment programs NK cell identity to meet the physiological demands of gestation. Competing Interest Statement The authors have declared no competing interest. Footnotes We performed additional experiments and clarified key points to address all of the reviewers' concerns. Pleas see revised Figures 1B, 1C, 1D, 2D, 2E, 5A-E, and Supplemental Figure 1. Abbreviations used in this paper include - cNK - conventional NK - Eomes - Eomesodermin - Gd - gestational day - ILC - innate lymphoid cell - ILC1 - type 1 innate lymphoid cell - TGF-β - transforming growth factor-β - trNK - tissue-resident NK - uNK - uterine NK