Up-and-down immunity of pregnancy in humans

One part of the human placenta in early pregnancy is particularly important for local immunity: the decidua basalis, which is transformed endometrium located at the site of embryo implantation. This placental bed tissue contains both maternal uterine immune cells, including decidual natural killer (NK) cells, the dominant leukocyte population exhibiting a unique phenotype, and fetal extravillous trophoblast which comes into direct contact with maternal decidual cells. To establish a successful placental development and healthy pregnancy outcome, the maternal immune system must tolerate paternal antigens expressed by trophoblast cells yet remain efficient for clearing any local pathogen infection. This review deals mainly with decidual NK cells. A key element, among others, to achieve such dual functions is the direct interaction between activating and inhibitory receptors expressed by decidual NK cells and their specific ligands presented by trophoblast or other decidual cells. Depending whether maternal decidual cells and trophoblast are infected by viruses, the balance between activating and inhibitory receptor signals mediated by decidual NK cell–trophoblast cross-talk results in tolerance (healthy pregnancy) or specific killing (pathogen-infected cells).

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A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

Immuno ◽

10.3390/immuno1030011 ◽

2021 ◽

Vol 1 (3) ◽

pp. 174-193

Author(s):

Jenny Valentina Garmendia ◽

Juan Bautista De Sanctis

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Embryo Implantation ◽

Inflammatory Cells ◽

Cell Physiology ◽

Therapeutic Approaches ◽

Pharmacological Modulation ◽

New Therapeutic Approaches ◽

Pharmacologic Modulation ◽

Inflammatory Burden

NK cells are lymphocytes involved in the innate and adaptative immune response. These cells are located in peripheral blood and tissues with ample functions, from immune vigilant to tolerogenic reactions. In the endometrium, NK cell populations vary depending on age, hormones, and inflammation. When pregnancy occurs, tissue-resident NK cells and conventional NK cells are recruited to protect the fetus, a tolerogenic response. On the contrary, in the inflamed endometrium, various inflammatory cells down-regulate NK tolerance and impair embryo implantation. Therefore, NK cells’ pharmacological modulation is difficult to achieve. Several strategies have been used, from progesterone, lipid emulsions to steroids; the success has not been as expected. However, new therapeutic approaches have been proposed to decrease the endometrial inflammatory burden and increase pregnancy success based on understanding NK cell physiology.

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Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy

Blood ◽

10.1182/blood-2007-08-105965 ◽

2008 ◽

Vol 111 (6) ◽

pp. 3108-3115 ◽

Cited By ~ 144

Author(s):

Claudia Carlino ◽

Helena Stabile ◽

Stefania Morrone ◽

Roberta Bulla ◽

Alessandra Soriani ◽

...

Keyword(s):

Cell Migration ◽

Nk Cells ◽

Chemokine Receptor ◽

Early Pregnancy ◽

Stromal Cells ◽

Nk Cell ◽

Distinct Pattern ◽

Cell Accumulation ◽

Decidual Cells ◽

Uterine Mucosa

Abstract During early pregnancy, uterine mucosa decidualization is accompanied by a drastic enrichment of CD56highCD16− natural killer (NK) cells. Decidual NK (dNK) cells differ from peripheral blood NK (pbNK) cells in several ways, but their origin is still unclear. Our results demonstrate that chemokines present in the uterus can support pbNK cell migration through human endothelial and stromal decidual cells. Notably, we observed that pregnant women's pbNK cells are endowed with higher migratory ability compared with nonpregnant women's or male donors' pbNK cells. Moreover, NK cell migration through decidual stromal cells was increased when progesterone-cultured stromal cells were used as substrate, and this correlated with the ability of progesterone to up-regulate stromal cell chemokine expression. Furthermore, we demonstrate that dNK cells migrate through stromal cells using a distinct pattern of chemokines. Finally, we found that pbNK cells acquire a chemokine receptor pattern similar to that of dNK cells when they contact decidual stromal cells. Collectively these results strongly suggest that pbNK cell recruitment to the uterus contributes to the accumulation of NK cells during early pregnancy; that progesterone plays a crucial role in this event; and that pbNK cells undergo reprogramming of their chemokine receptor profile once exposed to uterine microenvironment.

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Ovarian Stimulation Affects the Population of Mouse Uterine NK Cells at Early Pregnancy

BioMed Research International ◽

10.1155/2013/182531 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Parvin Dorfeshan ◽

Mojdeh Salehnia ◽

Seyed Mohammad Moazzeni

Keyword(s):

Nk Cells ◽

Ovarian Stimulation ◽

Nk Cell ◽

Embryo Implantation ◽

Control Group ◽

Tissue Samples ◽

Serum Gonadotropin ◽

Human Chorionic Gonadotropin Hormone ◽

Uterine Nk Cells ◽

Fertile Male

The aim of this study was to determine the influence of ovarian stimulation on endometrial mouse NK cell population. For superovulation, the female adult NMRI mice were injected i.p. with 10 IU of the pregnant mare serum gonadotropin followed 48 h later by an i.p. injection of 10 IU human chorionic gonadotropin hormone. Ovarian stimulated and nonstimulated mice were mated with fertile male. The presence of vaginal plug proved natural pregnancy, and this day was considered as day one of pregnancy. Tissue samples were prepared from the uterine horn and spleen of both groups of study on 7th day of pregnancy. Serum estradiol-17βand progesterone were measured at the same time. The tissue cryosections were prepared and double stained for CD 161 and CD3 markers, and NK cells population was analyzed. Relative frequency of NK cells was significantly lower in stroma and myometrium in hyperstimulated mice compared with the control group. However, no difference was seen in percentage of NK cells in spleen. The ovarian stimulation influences the proportion of uterine NK cells and may affect the embryo implantation.

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miRNAs in decidual NK cells: regulators worthy of attention during pregnancy

Reproductive Biology and Endocrinology ◽

10.1186/s12958-021-00812-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Liman Li ◽

Ting Feng ◽

Weijie Zhou ◽

Yuan Liu ◽

Hong Li

Keyword(s):

Nk Cells ◽

Molecular Mechanisms ◽

Expression Patterns ◽

Trophoblast Invasion ◽

Immune Functions ◽

Placental Development ◽

Rna Molecules ◽

Cell Functions ◽

Non Coding Rna ◽

Decidual Cells

AbstractThe critical immune effectors, including T, B, and natural killer (NK) cells, dendritic cells, and macrophages participate in regulating immune responses during pregnancy. Among these immune cells, decidual NK (dNK) cells are involved in key placental development processes at the maternal–fetal interface, such as uterine spiral artery remodeling, trophoblast invasion, and decidualization. Mechanistically, dNK cells significantly influence pregnancy outcome by secreting cytokines, chemokines, and angiogenic mediators and by their interactions with trophoblasts and other decidual cells. MicroRNAs (miRNAs) are small non-coding RNA molecules that participate in the initiation and progression of human diseases. Although the functions of circulating miRNAs in pathological mechanism has been extensively studied, the regulatory roles of miRNAs in NK cells, especially in dNK cells, have been rarely reported. In this review, we analyze the effects of miRNA regulations of dNK cell functions on the immune system during gestation. We discuss aberrant expressions of certain miRNAs in dNK cells that may lead to pathological consequences, such as recurrent pregnancy loss (RPL). Interestingly, miRNA expression patterns are also different between dNK cells and peripheral NK (pNK) cells, and pNK cells in the first- and third‐trimester of gestation. The dysregulation of miRNA plays a pivotal regulatory role in driving immune functions of dNK and pNK cells. Further understanding of the molecular mechanisms of miRNAs in dNK cells may provide new insights into the development of therapeutics to prevent pregnancy failure.

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108. FUNCTIONAL ROLE OF HtrA3 IN TROPHOBLAST CELL INVASION DURING HUMAN PLACENTAL DEVELOPMENT

Reproduction Fertility and Development ◽

10.1071/srb09abs108 ◽

2009 ◽

Vol 21 (9) ◽

pp. 27

Author(s):

H. Singh ◽

G. Nie

Keyword(s):

Cell Invasion ◽

Stromal Cells ◽

Functional Role ◽

First Trimester ◽

Trophoblast Cell ◽

Extravillous Trophoblast ◽

Placental Development ◽

Decidual Cells

Controlled invasion of extravillous trophoblast (EVT) through the maternal decidua is important for placental development and function. Serine protease HtrA3 is highly expressed in the decidual cells in the late secretory phase of the menstrual cycle and throughout pregnancy. It is highly expressed in first trimester in most trophoblast cell types, but not in the invading interstitial trophoblast. HtrA3 and its family members are down-regulated in a number of cancers and are proposed as tumor-suppressors. We hypothesized that HtrA3 is an inhibitor of trophoblast invasion and is down-regulated in invading EVTs, while up-regulation of decidual HtrA3 controls the process. The current study investigated HtrA3 expression in human endometrial stromal cells (HESC) during decidualization in vitro and whether HtrA3 inhibits EVT cell invasion. Stromal cells isolated from human endometrium were decidualized in vitro with estrogen, progesterone and cAMP. Quantitative RT-PCR and western showed HtrA3 mRNA and protein expression was significantly increased in decidualized HESC compared to controls. Indirect immunofluorescence showed homogeneous pattern and increase in intensity of HtrA3 staining in decidualized HESC compared to non-decidualized cells. HTR-8 cells derived from first trimester of pregnancy EVT showed higher levels of HtrA3 mRNA expression compared to other human choriocarcinoma cell lines (AC-1M88, AC-1M32, JEG-3 and BeWo). Both intracellular and extracellular HtrA3 staining was observed in HTR8 cells. Functional role of HtrA3 in cell invasion was determined in HTR-8 cells using an in vitro invasion assay. Exogenous addition of mutant HtrA3 (inhibitor) resulted in a significant increase in HTR-8 cells invading through matrigel coated membrane compared with controls. TGFβ-1 (as positive control) completely inhibited invasion of HTR-8 cells. HtrA3 is tightly regulated during decidualization of HESC in vitro. Inhibition of HtrA3 activity in trophoblastic HTR-8 cells increased invasiveness supporting its functional role during placental development.

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Uterine activin receptor-like kinase 5 is crucial for blastocyst implantation and placental development

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1514498112 ◽

2015 ◽

Vol 112 (36) ◽

pp. E5098-E5107 ◽

Cited By ~ 33

Author(s):

Jia Peng ◽

Diana Monsivais ◽

Ran You ◽

Hua Zhong ◽

Stephanie A. Pangas ◽

...

Keyword(s):

Transforming Growth Factor ◽

Nk Cell ◽

Conditional Knockout ◽

Major Type ◽

Female Reproduction ◽

Placental Development ◽

Activin Receptor ◽

Decidual Cells ◽

Unk Cells ◽

Receptor Like Kinase

Members of the transforming growth factor β (TGF-β) superfamily are key regulators in most developmental and physiological processes. However, the in vivo roles of TGF-β signaling in female reproduction remain uncertain. Activin receptor-like kinase 5 (ALK5) is the major type 1 receptor for the TGF-β subfamily. Absence of ALK5 leads to early embryonic lethality because of severe defects in vascular development. In this study, we conditionally ablated uterine ALK5 using progesterone receptor-cre mice to define the physiological roles of ALK5 in female reproduction. Despite normal ovarian functions and artificial decidualization in conditional knockout (cKO) mice, absence of uterine ALK5 resulted in substantially reduced female reproduction due to abnormalities observed at different stages of pregnancy, including implantation defects, disorganization of trophoblast cells, fewer uterine natural killer (uNK) cells, and impairment of spiral artery remodeling. In our microarray analysis, genes encoding proteins involved in cytokine–cytokine receptor interactions and NK cell-mediated cytotoxicity were down-regulated in cKO decidua compared with control decidua. Flow cytometry confirmed a 10-fold decrease in uNK cells in cKO versus control decidua. According to these data, we hypothesize that TGF-β acts on decidual cells via ALK5 to induce expression of other growth factors and cytokines, which are key regulators in luminal epithelium proliferation, trophoblast development, and uNK maturation during pregnancy. Our findings not only generate a mouse model to study TGF-β signaling in female reproduction but also shed light on the pathogenesis of many pregnancy complications in human, such as recurrent spontaneous abortion, preeclampsia, and intrauterine growth restriction.

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Increased surveillance of cells in mitosis by human NK cells suggests a novel strategy for limiting tumor growth and viral replication

Blood ◽

10.1182/blood-2006-07-036509 ◽

2006 ◽

Vol 109 (2) ◽

pp. 670-673 ◽

Cited By ~ 22

Author(s):

Esther N. M. Nolte–'t Hoen ◽

Catarina R. Almeida ◽

Nadia R. Cohen ◽

Shlomo Nedvetzki ◽

Helen Yarwood ◽

...

Keyword(s):

Cell Cycle ◽

Nk Cells ◽

Cell Cycle Progression ◽

Nk Cell ◽

Direct Interaction ◽

Cycle Progression ◽

Cell Receptors ◽

Viral Genomes ◽

Nk Cell Receptors ◽

Novel Strategy

Abstract The threat from cancer cells is inherently linked to cell-cycle progression, and viral genomes commonly replicate, for example, within episomes or proviruses, during mitosis. We report here that human natural killer (NK) cells bound cells in mitosis and attacked pathogenic cells in mitosis more effectively than the same cells in other stages of the cell cycle. Thus, cells in mitosis warrant and undergo heightened surveillance, a novel strategy for immunologic assessment of danger. Recognition of cells in mitosis involved ligation of activating NK-cell receptors and binding to target-cell hyaluronan, a component of the pericellular matrix known to be increased during mitosis. Direct interaction between activating NK-cell receptors and hyaluronan is possible, but other mechanisms consistent with our data are also discussed.

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Regulation of CX3CL1 Expression in Human First-Trimester Decidual Cells: Implications for Preeclampsia

Reproductive Sciences ◽

10.1177/1933719118815592 ◽

2019 ◽

Vol 26 (9) ◽

pp. 1256-1265 ◽

Cited By ~ 4

Author(s):

S. Joseph Huang ◽

Chie-Pein Chen ◽

Lynn Buchwalder ◽

Ya-Chun Yu ◽

Longzhu Piao ◽

...

Keyword(s):

Protein Kinase ◽

Nk Cells ◽

Nk Cell ◽

First Trimester ◽

Mitogen Activated Protein Kinase ◽

Decidual Cells ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Ifn Γ ◽

Protein Kinase Kinase

C-X3-C motif ligand 1 (CX3CL1) mediates migration, survival, and adhesion of natural killer (NK) cells, monocytes, and T-cells to endothelial/epithelial cells. Aberrant numbers and/or activation of these decidual immune cells elicit preeclampsia development. Decidual macrophages and NK cells are critical for implantation, while macrophage-derived tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and NK cell-derived interferon-γ (IFN-γ) are associated with preeclampsia development. Thus, serum and decidual levels of CX3CL1 from first-trimester pregnancy and preeclampsia-complicated term pregnancy were examined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The effects of incubating primary human first-trimester decidual cells (FTDCs) with estradiol + medroxyprogesterone acetate + either IL-1β or TNF-α and/or IFN-γ on CX3CL1 expression were also assessed by quantitative reverse transcription-polymerase chain reaction and ELISA. The inhibition of each signaling pathway with each kinase and nuclear factor κB (NFκB) inhibitors was evaluated by ELISA. Chemotaxis of CD56brightCD16− NK cells by various concentrations of CX3CL1 was evaluated. C-X3-C motif ligand 1 is expressed by both cytotrophoblasts and decidual cells in first-trimester decidua. C-X3-C motif ligand 1 expression is increased in term decidua but unchanged in first-trimester and term serum of patients with preeclampsia. Interferon-gamma and either IL-1β or TNF-α synergistically upregulated CX3CL1 expression in FTDCs. Coincubation with IL-1β or TNF-α or IFN-γ, mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), c-JUN N-terminal kinase (JNK), and NFκB inhibitors suppressed CX3CL1 production. C-X3-C motif ligand 1 elicited concentration-dependent enhancement of CD56brightCD16− NK cell migration. In conclusion, the current study suggests that decidual cell-secreted CX3CL1 is involved in the later development of preeclampsia, whereas circulating CX3CL1 levels do not predict preeclampsia. Mitogen-activated protein kinase kinase 1 and 2, JNK, and NFκB signaling mediate IL-1β-, TNF-α-, and IFN-γ-induced CX3CL1 production by FTDCs.

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