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Successful pregnancy requires a series of coordinated interactions between the developing placenta, the uterus, and the maternal immune system (1). At the maternal/fetal interface, where the placenta contacts the uterus, a specialized type of lymphocyte known as a uterine natural killer (uNK) cell is thought to play a critical role in mediating the uterine vascular adaptations to pregnancy. Epidemiological data have suggested that this function is modified by the response of uNK cells to the paternally inherited classical class I major histocompatibility complex (MHC I) molecules (i.e., the HLA-A, -B, and -C antigens in humans) expressed by placental trophoblasts invading into the uterus, as inopportune genetic combinations of the mother and father expected to alter uNK cell activity increase the risk of certain obstetrical complications (i.e., preeclampsia, fetal growth restriction, and recurrent miscarriage). In mice, however, direct evidence for such uNK cell-mediated “allorecognition” of the placenta has so far been lacking, and as a result the biomedical researcher's favorite model organism has yet to be used to study how levels of uNK cell activity influence reproductive success. In PNAS, Hemberger and colleagues now present strong evidence that murine uNK cells do indeed recognize paternal MHC I molecules expressed by invasive trophoblasts and that this recognition has significant implications for uterine vascular remodeling and ultimate pregnancy outcome (2). This work thus opens up use of the mouse as a means to study the key interactions that underlie some of the more serious complications of pregnancy. The work of Madeja et al. follows on a series of studies implicating uNK cells as important mediators of the developmental interactions between the placenta and the uterus that establish the placenta as a high-capacity nutrient and gas exchange organ. In both mice and humans, uNK cells have long been known to constitute the vast majority …

Strangers no more: Uterine NK cell recognition of the placenta in mice