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

Abstract

Early 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.

Figure 1

Fetal–maternal interface. Floating chorionic villous trophoblast tree carrying fetal blood vessels is bathed in maternal blood. Invasive extravillous trophoblasts (EVTs) invade the maternal decidua and are in direct contact with the maternal immune system. By secreting several cytokines/chemokines and proangiogenic factors, decidual natural killer (dNK) cells promote the invasion of EVT, vascular remodelling and help in the establishment of fetal tolerance. Other cells are present at the maternal decidual including regulatory T (Treg) cells, γδ T cells and tolerogenic dendritic cells.

Figure 2

Natural killer cell receptors expressed on decidual natural killer (dNK) cells. Most dNK cells express high levels of activating receptors including the Natural Cytotoxicity Receptors (NKp30, NKp44, NKp46), NKG2D, CD94/NKG2C-E. They also express inhibitory receptors such as 2B4, NKG2A/B, KIR2DLs and ILT2. Known and unknown (?) cellular ligands are listed above each receptor. B7H6? And MLS5? are putative ligands for NKp30 and NKp44 activating receptors. NKP46 receptor recognizes a yet unidentified cellular ligand (?). Most of the activating receptors have a short intracytoplasmic tail and require the recruitment of adaptor molecules such as DAP10/12 or CD3ζ in order to transduce the activating signals. Inhibitory receptors possess one or more inhibitory motifs in their intra-cytoplasmic domain.

Figure 3

Decidual natural killer (dNK) cell adaptations during normal pregnancy and congenital cytomegalovirus infection: dNK cells are fully armed with cytotoxic granules enriched in granzymes and perforin (CG). During healthy pregnancy dNK cells secrete large amounts of soluble factors that participate in all processes necessary for placentation. NK cell cytotoxicity is under negative signals emanating from ligation of HLA-C and HLA-E and NKG2D ligand (?) represented by either MICA/B or ULBPs expressed on fetal trophoblast (cell in blue) to their respective inhibitory KIR and NKG2A receptors. In the case of human cytomegalovirus (HCMV) infection, dNK cells are able to recognize stress signals expressed on infected cells (yellow). They form immunological synapses, polarize their actin filament (FA), and orient their microtubule organizing centre (MTOC) and lytic granules to the synaptic area.