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Combinations of KIR and HLA genes associate with pregnancy complications as well as with many other clinical scenarios. Understanding how certain KIR and HLA genes influence the biology of a disease is, however, a formidable challenge. These are the two most variable gene families in the human genome. Moreover, the biology of a disease is best understood by studying the cells of the affected tissue. Natural Killer (NK) cells express KIR and are the most abundant leukocytes in the uterus. Most of our knowledge of NK cells is based on what we have learned from cells isolated from blood, but these are different from their tissue resident counterparts, including uterine NK (uNK) cells. Reproductive immunology faces an additional challenge: Two genotypes must be considered because both maternal and foetal HLA class I molecules may influence the outcome of pregnancy, most likely through interactions with maternal KIR expressed on uNK cells. Maternal uNK cells are not spontaneously cytotoxic and instead engage in interactions with trophoblast. We hypothesise that these interactions regulate allocation of resources between the foetus and the mother and may go wrong in diseases of pregnancy.

Pregnancy presents an immunological conundrum because two genetically different individuals coexist. The maternal lymphocytes at the uterine maternal-fetal interface that can recognize mismatched placental cells are T cells and abundant distinctive uterine NK (uNK) cells. Multiple mechanisms exist that avoid damaging T cell responses to the fetus, whereas activation of uNK cells is probably physiological. Indeed, genetic epidemiological data suggest that the variability of NK cell receptors and their MHC ligands define pregnancy success; however, exactly how uNK cells function in normal and pathological pregnancy is still unclear, and any therapies aimed at suppressing NK cells must be viewed with caution. Allorecognition of fetal placental cells by uNK cells is emerging as the key maternal-fetal immune mechanism that regulates placentation.

Our understanding of development and function of natural killer (NK) cells has progressed significantly in recent years. However, exactly how uterine NK (uNK) cells develop and function is still unclear. To help investigators that are beginning to study tissue NK cells, we summarize in this review our current knowledge of the development and function of uNK cells, and what is yet to be elucidated. We compare and contrast the biology of human and mouse uNK cells in the broader context of the biology of innate lymphoid cells and with reference to peripheral NK cells. We also review how uNK cells may regulate trophoblast invasion and uterine spiral arterial remodeling in human and murine pregnancy.

Tamara Tilburgs (Harvard University, Cambridge, US and now at the Cincinnati Children's Hospital, US) discussed the delicate balance that the maternal immune system must strike between fetal tolerance and antiviral immunity. Anthony De Tomaso (University of California Santa Barbara, US) talked about the strange and fascinating life of a basal chordate that uses allorecognition to regulate stem cell parasitism. Despite not present at the course, Stephen Tukwasibwe, then a research assistant in the same hospital of faculty member Annettee Nakimuli, became interested in the immunogenetics of pregnancy. Having worked successfully on the genetics of resistance to malaria and secured a Wellcome Trust PhD grant, Stephen started his thesis at Makerere University under the supervision of Annettee Nakimuli and my co-mentorship, to test the hypothesis that Plasmodium may have selected for those genetic variants that may protect from malaria but expose women to pregnancy complications in SSA.

Mammalian reproductive performance declines rapidly with advanced maternal age. This effect is largely attributed to the exponential increase in chromosome segregation errors in the oocyte with age. Yet many pregnancy complications and birth defects that become more frequent in older mothers, in both humans and mice, occur in the absence of karyotypic abnormalities. Here, we report that abnormal embryonic development in aged female mice is associated with severe placentation defects, which result from major deficits in the decidualisation response of the uterine stroma. This problem is rooted in a blunted hormonal responsiveness of the ageing uterus. Importantly, a young uterine environment can restore normal placental as well as embryonic development. Our data highlight the pivotal, albeit under-appreciated, impact of maternal age on uterine adaptability to pregnancy as major contributor to the decline in reproductive success in older females. Advanced maternal age has been associated with lower reproductive success and higher risk of pregnancy complications. Here the authors show that maternal ageing-related embryonic abnormalities in mouse are caused by decidualisation and placentation defects that can be rescued by transferring the embryo from an old to a young uterus.

Innate lymphoid cells (ILCs) are the most abundant immune cells in the uterine mucosa both before and during pregnancy. Circumstantial evidence suggests they play important roles in regulating placental development but exactly how they contribute to the successful outcome of pregnancy is still unclear. Uterine ILCs (uILCs) include subsets of tissue-resident natural killer (NK) cells and ILCs, and until recently the phenotype and functions of uILCs were poorly defined. Determining the specific roles of each subset is intrinsically challenging because of the rapidly changing nature of the tissue both during the menstrual cycle and pregnancy. Single-cell RNA sequencing (scRNAseq) and high dimensional flow and mass cytometry approaches have recently been used to analyse uILC populations in the uterus in both humans and mice. This detailed characterisation has significantly changed our understanding of the heterogeneity within the uILC compartment. It will also enable key clinical questions to be addressed including whether specific uILC subsets are altered in infertility, miscarriage and pregnancy disorders such as foetal growth restriction and pre-eclampsia. Here, we summarise recent advances in our understanding of the phenotypic and functional diversity of uILCs in non-pregnant endometrium and first trimester decidua, and review how these cells may contribute to successful placental development.

Reduced trophoblast invasion and vascular conversion in decidua are thought to be the primary defect of common pregnancy disorders including preeclampsia and fetal growth restriction. Genetic studies suggest these conditions are linked to combinations of polymorphic killer cell Ig-like receptor (KIR) genes expressed by maternal decidual NK cells (dNK) and HLA-C genes expressed by fetal trophoblast. Inhibitory KIR2DL1 and activating KIR2DS1 both bind HLA-C2, but confer increased risk or protection from pregnancy disorders, respectively. The mechanisms underlying these genetic associations with opposing outcomes are unknown. We show that KIR2DS1 is highly expressed in dNK, stimulating strong activation of KIR2DS1+ dNK. We used microarrays to identify additional responses triggered by binding of KIR2DS1 or KIR2DL1 to HLA-C2 and found different responses in dNK coexpressing KIR2DS1 with KIR2DL1 compared with dNK only expressing KIR2DL1. Activation of KIR2DS1+ dNK by HLA-C2 stimulated production of soluble products including GM-CSF, detected by intracellular FACS and ELISA. We demonstrated that GM-CSF enhanced migration of primary trophoblast and JEG-3 trophoblast cells in vitro. These findings provide a molecular mechanism explaining how recognition of HLA class I molecules on fetal trophoblast by an activating KIR on maternal dNK may be beneficial for placentation.

During early pregnancy, decidual innate lymphoid cells (dILCs) interact with surrounding maternal cells and invading fetal extravillous trophoblasts (EVT). Here, using mass cytometry, we characterise five main dILC subsets: decidual NK cells (dNK)1–3, ILC3s and proliferating NK cells. Following stimulation, dNK2 and dNK3 produce more chemokines than dNK1 including XCL1 which can act on both maternal dendritic cells and fetal EVT. In contrast, dNK1 express receptors including Killer-cell Immunoglobulin-like Receptors (KIR), indicating they respond to HLA class I ligands on EVT. Decidual NK have distinctive organisation and content of granules compared with peripheral blood NK cells. Acquisition of KIR correlates with higher granzyme B levels and increased chemokine production in response to KIR activation, suggesting a link between increased granule content and dNK1 responsiveness. Our analysis shows that dILCs are unique and provide specialised functions dedicated to achieving placental development and successful reproduction. As an interface between maternal and fetal tissues, decidua hosts immune cells specialized in fostering a successful pregnancy. Here the authors carry out high-dimensional characterization of function, morphology and surface markers of human decidual innate lymphoid cells (ILCs), identifying subsets with features distinct from blood ILC.

Maternal immune cells interact with the placenta and influence pregnancy complications Various factors contribute to the hypertensive placental disease preeclampsia, fetal growth restriction (FGR), spontaneous abortion, preterm labor, and stillbirth. Some of these problems are due to placental dysfunction ( 1 ). The placenta attaches to and invades deep into the decidua, the specialized uterine mucosa that is rich in maternal immune cells. Because the placenta is formed from the fetus and contains genetic material from another individual (the father), it should be targeted by the maternal immune system but it usually is not. By understanding the interactions between the placenta and the maternal immune system, interventions to improve pregnancy outcomes could be developed.

Ion channels, exchangers and pumps are expressed ubiquitously in cells from all phyla of life. In mammals, their role is best described in excitable cells, where they regulate the initiation and propagation of action potentials. There are over 70 different types of K + channels subunits that contribute to these processes. In non-excitable cells, K + channels set the resting membrane potential, which in turn drives the activity of other translocators. K + channels also help maintain cell volume, influence cell proliferation and apoptosis and regulate Ca 2+ signaling, which in turn is crucial for many cellular processes, including metabolism, secretion, and gene expression. K + channels play crucial roles in the activation, proliferation and a variety of other functions in cells of the innate and adaptive immune system. The ATP-sensitive K + (K ATP ) channel has an established role in diverse cells, but its presence and function in immunity is scantly described. Public gene expression databases show that K ATP channel subunits are highly expressed in NKT and NK cells, and that they are significantly upregulated after infection in CD8+ T cells and macrophages. We discuss these findings in the light of the available literature and propose a role for K ATP channels in cytotoxicity of cells that are primed for a rapid immune response. Possible underlying molecular mechanisms are discussed.