The up side of decidual natural killer cells: new developments in immunology of pregnancy

Abstract

SummaryEarly phases of human pregnancy are associated with the accumulation of a unique subset of natural killer (NK) cells in the maternal decidua. Decidual NK (dNK) cells that are devoid of cytotoxicity play a pivotal role in successful pregnancy. By secreting large amounts of cytokines/chemokines and angiogenic factors, dNK cells participate in all steps of placentation including trophoblast invasion into the maternal endometrium and vascular remodelling. In this review, we summarize some of dNK cell features and discuss more recent exciting data that challenge the conventional view of these cells. Our new data demonstrate that dNK cells undergo fine tuning or even subvert their classical inhibitory machinery and turn into a real defence force in order to prevent the spread of viruses to fetal tissue. Today it is not clear how these phenotypic and functional adaptations impact cellular cross-talk at the fetal-maternal interface and tissue homeostasis. Ultimately, precise understanding of the molecular mechanisms that govern dNK cell plasticity during congenital human cytomegalovirus infection should lead to the design of more robust strategies to reverse immune escape during viral infection and cancer.Keywords: cytomegalovirus; decidua; natural killer cells; pregnancy.Natural killer (NK) cells are large granular lymphocytes of the innate immune system and represent the first line in the host defence against invading pathogens.1,2 Unlike T cells, NK cells do not express an antigen-specific receptor but rather they express a large repertoire of activating and inhibitory receptors. Mature NK cells recirculate in the blood (pNK) where their number varies anywhere from 5 to 20% of total lymphocytes. Natural killer cells are also present in lymphoid and non-lymphoid tissues including the uterus where they are mainly CD56 bright CD16 neg . 3 Given the fact that these cells are fully armed with cytolytic granules that can cause great harm, their activation is regulated by germline-encoded inhibitory or activating cell surface receptors that recognize self-ligands or pathogen-induced and stress-induced ligands. 4 The net balance between activating and inhibitory signals would determine the outcome of NK cell responses against various threats. Activation of NK cells is inhibited mainly after interaction of inhibitory receptors with MHC class I molecules. However, the loss of MHC class I expression is not sufficient to trigger NK cell responsiveness because additional activating signals are required. 5 The NK cells can eliminate their target through different mechanisms, including direct cell cytotoxicity or cytokine production. Besides their role as effectors of innate immunity, NK cells play a pivotal role in bridging the innate and adaptive arms of the immune system. By secreting large amounts of cytokines and chemokines, NK cells impact dendritic cell maturation 6,7 and antigen-specific adaptive immune responses. 8,9 During pregnancy, a special population of NK cells accumulates within the endometrium, which constit...

Hepatitis C Virus Sensing by Human Trophoblasts Induces Innate Immune Responses and Recruitment of Maternal NK Cells: Potential Implications for Limiting Vertical Transmission

“…The first trimester of pregnancy is characterized by high numbers of dNK cells within the decidua, perhaps accounting for the low rate of congenital cytomegalovirus (CMV) infection (25). It has been shown that NK cells that infiltrate during the first trimester can switch their phenotype after sensing infection and that dNK cells can be found in the vicinity of infected cells within floating chorionic villi (59).…”

“…The ability to cross the placental barrier is one key determinant of invasive viruses and pathogens. Little is known about the ability of dNK cells to provide protective immunity against these agents (25). …”

Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

“…Natural killer cells from decidual tissue in pregnant uterus (dNK) have unique phenotypical and functional properties compared to NK cells found in peripheral blood (pNK) (103). Mouse studies originally demonstrated that dNK cells function to support embryo implantation by secretion of numerous factors, including IFN-γ, to promote angiogenesis and trophoblast invasion (104).…”

Chronic infusion of interleukin‐17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats

“…Decidual NK cells have been recognized as a distinct subtype with these cells comprising nearly 40 % of decidual cells in early pregnancy before decreasing to low levels by the last trimester (Sargent et al. ; Jabrane‐Ferrat and Siewiera ). They are distinct in that they show little cytolytic activity, are major secretors of angiogenic and trophoblast attracting cytokines such as VEGF, IL‐8, and IL‐10, and play an important role in promoting tolerance to cytotrophoblasts and directing their invasion of and subsequent remodeling of maternal vessels in the myometrium and endometrium (Hanna et al.…”