Barahona, J. D. | Search bioRxiv

bioRxiv2025

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

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-{beta}-dependent differentiation pathway by which circulating conventional NK cells convert into uterine tissue-resident NK cells during murine pregnancy. Loss of TGF-{beta} receptor II expression in Ncr1-expressing cells disrupted this conversion, markedly reducing tissue-resident NK cells in the gravid uterus. Impaired TGF-{beta}-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-{beta} 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.

immunology↗

bioRxiv2025

Eomesodermin defines uterine NK cells crucial for pregnancy success in mice

Uterine natural killer cells have been thought to be critical for reproductive success, and their developmental origins remain unclear. Here, we demonstrate that Eomesodermin is a key transcription factor determining the lineage of tissue-resident NK cells within the uterus both at steady-state and during pregnancy. Ablation of Eomesodermin in Ncr1-expressing cells results in the loss of tissue-resident NK cells in both the virgin and pregnant uterus, suggesting that uterine tissue-resident NK cells derive from precursors in the conventional NK cell lineage. We further show that the genetic absence of uterine NK cells during murine gestation leads to adverse pregnancy outcomes marked by reduced litter sizes and increased resorption rates. Collectively, our data underscore the pivotal role of uNK cells in pregnancy and offer novel insights into their lineage specification, revealing Eomesodermin as a crucial factor in their establishment.

immunology↗