TGF-β drives uterine tissue-resident NK cell differentiation crucial for murine pregnancy 2309469

Abstract Introduction Conventional natural killer (cNK) cells differentiate in response to tissue-specific cues, generating specialized NK cell subsets. Within the uterus, this process gives rise to uterine NK cells (uNK), a heterogeneous population largely composed of tissue-resident NK (trNK) cells. Our prior work shows that uNK cells are critical for reproductive success, as their absence results in adverse pregnancy outcomes in mice. However, the molecular cues mediating uterine trNK cell differentiation remain poorly understood. TGF-β is abundant in uterine tissues and has been implicated in immune cell differentiation. We therefore hypothesized that TGF-β drives the differentiation of peripheral cNK cells into uterine trNK cells to support pregnancy. Methods To test this, we generated mice lacking TGF-β receptor II in Ncr1+ NK cells by crossing TGF-βRIIfl/fl with Ncr1icre mice. We then characterized innate lymphoid cell subsets in the pregnant uterus of TGF-βRIINcr1Δ and littermate dams using flow cytometry. Pregnancy outcomes were assessed by evaluating spiral artery morphology, fetal resorption at midgestation, and litter size at birth. Splenic cNK cells were adoptively transferred into TGF-βRIINcr1Δ dams to restore the uterine trNK cell population. Results We found that peripheral cNK cells extravasate into the gravid murine uterus, where they adopt a trNK cell phenotype. Loss of TGF-βRII in Ncr1+ cells profoundly disrupted this conversion, significantly reducing uterine trNK cells during gestation. Impaired TGF-β—dependent uterine trNK cell differentiation resulted in defective spiral artery remodeling and increased fetal resorption at midgestation, ultimately reducing litter sizes at birth. Restoration of uterine trNK cells rescued fetal viability at midgestation. Conclusion This study defines a pivotal role for TGF-β signaling in directing peripheral cNK cells to become uterine trNK cells during murine pregnancy and highlights the physiologic importance of this conversion for reproductive success. Funding Source n/a Topic Categories Mucosal and Regional Immunology (MUC)