重度子痫前期蜕膜NK细胞Tim-3的表达及其相关作用

目的 探讨重度子痫前期Tim-3+CD56+CD16-NK细胞的表达及其对滋养细胞侵袭及血管内皮细胞成管能力的影响.方法 分离重度子痫前期患者(sPE组)及正常妊娠孕产妇(Normal组)的胎盘蜕膜组织中单个核细胞,细胞流式检测蜕膜NK细胞(decidual NK cell,dNK)细胞所占比例;免疫磁珠分选CD56+...     

The decidual gamma-delta T cells up-regulate the biological functions of trophoblasts via IL-10 secretion in early human pregnancy

The functions of decidual γδT cells in early human pregnancy are not fully understood. The present study was undertaken to characterize the action of decidual γδT cells, and analyze their regulatory roles in proliferation and invasion of trophoblasts in early human pregnancy. It was revealed that decidual γδT cells were a CD4⁻ and CD8⁻ subset whose numbers increased significantly in either the decidua or peripheral blood. The main cytokines synthesized in decidual γδT cells in decreasing concentration were; IL-10 > TGF-β > TNF-α ≥ IFN-γ, with little IL-2 or IL-4 being produced. Decidual γδT cells promoted trophoblast proliferation and invasion, and suppressed trophoblast apoptosis through IL-10 secretion in co-culture. These results suggest that γδT cells in human decidua might play an important role in the Th2 bias at maternal–fetal interface and in the development and progression of the placenta, which is beneficial to maternal immunotolerance toward the fetus in early human pregnancy.     

Sperm with damaged membranes are profoundly at risk to have caspases 8, 9 and 3 activated

PROBLEM:  It is almost dogma that IL-2 is not expressed at the M–F interface during normal pregnancy. However, recent results by ours and others clearly showed that IL-15-Th1 type cytokine which shares many similarities with IL-2 is expressed at the interface. IL-15 can affect cytolytic activity of maternal decidual lymphocytes which heavily infiltrate maternal decidua during the first trimester pregnancy. These cells are in a direct contact with trophoblastic cells. IL-18 is a recently discovered Th1 type cytokine with many interesting functions. The aim is to examine IL-18 distribution at the interface and its potential in up-regulating peripheral blood (PB) and decidual lymphocytes (DL) cytotoxicity. Th1 activated lymphocytes are LAK cells and they can kill by both Perforin and Fas pathways in non MHC restricted manner.
METHODS:  PBL and DL were obtained from elective pregnancy termination of pregnancy. IL-18 and IL-18R expression was detected by flow cytometry and immunohistology and cytolytic potential by cytotoxicity against K-562 (NK sensitive) and P815 (NK resistant) cell lines.
RESULTS:  IL-18 positive cells were found in the suspension of Decidual adherent cells and IL-18 R expressions at the trophoblastic cells of villi. Both IL-15 and IL-18 are increasing cytolytic potential of PBL and DL against NK sensitive cell line. Decidual lymphocytes are activated cells with the potential of killing NK resistant but LAK sensitive lines and this is mediated by both perforin and Fas pathways.
CONCLUSIONS:  Physiological and pathophysio- logical role(s) of cytolytic pathways and Th1 cytokines (IL-15 and IL-18) at the interface will be discussed.     

The expression of human leukocyte antigen-G on trophoblasts abolishes the growth-suppressing effect of interleukin-2 towards them

PROBLEM: We have shown the attenuated human leukocyte antigen (HLA)-G expression on trophoblasts and an aberrant expression of interleukin (IL)-2, a cytotoxic cytokine, in decidual tissue in preeclampsia, where deteriorated trophoblastic invasion into decidual layers may constitute a crucial pathogenesis. We hypothesized that the absence of HLA-G might make trophoblasts susceptible to compromise by IL-2. METHOD OF STUDY: We analyzed the growth of HLA-G-negative and positive cell lines, all of which possessed IL-2 receptors, in the culture with or without IL-2 supplementation. RESULTS: The proliferation of HLA-G positive trophoblastic cell lines (BeWo and JEG-3) was not influenced by the addition of IL-2, whereas a HLA-G-negative trophoblastic cell line (JAR) exhibited significantly decreased proliferation when cultured with IL-2. Interestingly, the transfection of JAR cells with HLA-G completely eliminates the growth-inhibitory effect of IL-2. CONCLUSION: The expression of HLA-G may commit trophoblasts to evade cell damage by IL-2, which may be relevant to maternal tolerance of the fetus during pregnancy and its derangement as exemplified by preeclampsia.     

人母-胎界面滋养细胞来源的CXCL16促进蜕膜γδT细胞产生IL-10及TGF-β

目的:探讨人早孕滋养细胞通过CXCL16/CXCR6途径对蜕膜γδT细胞分泌细胞因子功能的影响。方法:临床收集正常早孕妇女绒毛组织及蜕膜组织各10例,体外分离蜕膜γδT细胞和滋养细胞,原代培养滋养细胞12、24、48、72、96小时,ELISA检测培养上清中CXCL16的浓度;RT-PCR检测蜕膜γδT细胞中CXCR6的表达;建立人早孕蜕膜γδT细胞与滋养细胞的共培养体系,同时加或不加CXCL16的中和性抗体,或者γδT细胞与滋养细胞间接共培养,48小时后流式细胞术检测γδT细胞中IL-10和TGF-β的表达。结果:人早孕滋养细胞能够分泌CXCL16,且其浓度呈现时间累积效应;蜕膜γδT细胞则表达CXCR6。与滋养细胞直接共培养后,γδT细胞表达IL-10和TGF-β显著增高,且明显高于间接共培养组,加入CXCL16的中和性抗体后,IL-10和TGF-β的增加效应被部分抵消。结论:人早孕滋养细胞通过分泌CXCL16促进表达CXCR6的蜕膜γδT细胞产生IL-10和TGF-β,从而可能有利于妊娠期母-胎界面Th2型偏移,进而有利于正常妊娠的维持。     

Preeclampsia-related inflammatory cytokines regulate interleukin-6 expression in human decidual cells

Preeclampsia, a common pregnancy disorder associated with an increase in systemic inflammation, is the leading cause of maternal and fetal morbidity and mortality throughout the world. It is associated with shallow extravillous trophoblast invasion of the decidua, leading to uteroplacental blood flow that is inadequate for the developing fetal-placental unit. In preeclamptic women, interleukin-6 (IL-6) levels in plasma, but not placenta, are elevated, prompting evaluation of the decidua as a potential source of this excess, circulating IL-6. The current study found significantly higher immunohistochemical staining for IL-6 in decidual cells from preeclamptic versus preterm, gestational age-matched control placentas. Pro-inflammatory cytokines associated with the genesis of preeclampsia (i.e., tumor necrosis factor-alpha and interleukin-1beta) enhanced IL-6 mRNA levels and increased secreted IL-6 levels in first trimester leukocyte-free decidual cell incubations, as measured by real time quantitative RT-PCR, ELISA, and Western blotting. Therefore, decidual cell-derived IL-6 may contribute to excess circulating IL-6 levels that can promote both endothelial cell dysfunction (and subsequent vascular dysfunction) and the pathogenesis of preeclampsia whereas locally elevated IL-6 levels may contribute to an excess of decidual macrophages implicated in shallow extravillous trophoblast invasion of the decidua.     

Phenotypic Analysis of Adhesion Molecules in First-Trimester Decidual Tissue From Chorion Villus Samples

PROBLEM: First-trimester decidua contain CD56^bright /CD16^neg lymphocytes that phenotypically resemble a subset of peripheral blood natural killer (NK) cells. Factors controlling their localization to decidua are unknown, but they may relate to trophoblast invasion, endometrial decidualization, and adhesion molecule expression. METHOD OF STUDY: Ninety-one chorion villous samples (CVS) were screened for the presence of decidua, and selected specimens were analyzed for the expression of adhesion molecule pairs using a panel of monoclonal antibodies. RESULTS: Lymphoid cells in CVS-derived decidua expressed CD56, PECAM, intracellular adhesion molecule-1 (ICAM-1), and the integrins LFA-1, αEβ7, and α4β1, and co-receptors for these molecules were expressed by decidual stromal cells, invasive trophoblasts, and venule endothelium. Some endothelium expressed a cuboidal phenotype. CONCLUSIONS: The expression of complimentary pairs of adhesion molecules by maternal lymphoid cells and by either extravillous cytotrophoblast or decidual stromal cells supports the hypothesis that these cells interact within decidua. Also, both LFA-1 and α4β1 may contribute to decidual localization of CD56^bright NK cells.     

Leukocyte driven-decidual angiogenesis in early.pregnancy

Successful pregnancy and long-term, post-natal maternal and offspring cardiac, vascular and metabolic health require key maternal cardiovascular adaptations over gestation. Within the pregnant decidualizing uterus, coordinated vascular, immunological and stromal cell changes occur. Considerable attention has been given to the roles of uterine natural killer （uNK） cells in initiating decidual spiral arterial remodeling, a process normally completed by mid-gestation in mice and in humans. However, leukocyte roles in much earlier, region specific, decidual vascular remodeling are now being defined. Interest in immune cell-promoted vascular remodeling is driven by vascular aberrations that are reported in human gestational complications such as infertility, recurrent spontaneous abortion, preeclampsia （PE） and fetal growth restriction. Appropriate maternal cardiovascular responses during pregnancy protect mothers and their children from later cardiovascular disease risk elevation. One of the earliest uterine responses to pregnancy in species with hemochorial placentation is stromal cell decidualization, which creates unique niches for angiogenesis and leukocyte recruitment. In early decidua basalis, the aspect of the implantation site that will cradle the developing placenta and provide the major blood vessels to support mature placental functions, leukocytes are greatly enriched and display specialized properties. UNK cells, the most abundant leukocyte subset in early decidua basalis, have angiogenic abilities and are essential for normal early decidual angiogenesis. The regulation of uNK cells and their roles in determining maternal and progeny cardiovascular health over ore~nancv and PostPartum are discussed.     

Expression on cells of early human pregnancy decidua, of the p75, IL-2 and p145, IL-4 receptor proteins.

Immunohistological studies of human first trimester pregnancy decidua demonstrated the presence of the p75 interleukin-2 receptor (IL-2R) and the p145 interleukin-4 receptor protein (IL-4R) on cells in the decidual stroma; there was no expression of CD25, the p55 IL-2R. The IL-4R was also expressed on the basal face of the glandular epithelial cells. Flow cytometric analysis of antibody-labelled decidual cell dispersions confirmed these results. Double antibody labelling demonstrated that p75 was expressed exclusively on the CD56-positive decidual large granular lymphocytes (LGL), whereas the IL4-R was expressed on some decidual LGL, and most decidual macrophages and T cells. In vitro incubation of decidual cells with IL-2 failed to induce expression of p55 or to increase the expression of either p75 or the p145 IL-4R. Purified decidual LGL proliferated in vitro in response to IL-2, and IL-4 inhibited this IL-2-induced proliferation.     

Maternal IL-11Rα function is required for normal decidua and fetoplacental development in mice

In eutherian mammals, implantation and establishment of the chorioallantoic placenta are essential for embryo development and survival. As a maternal response to implantation, uterine stromal cells proliferate, differentiate, and generate the decidua, which encapsulates the conceptus and forms the maternal part of the placenta. Little is known about decidual functions and the molecular interactions that regulate its development and maintenance. Here we show that the receptor for the cytokine interleukin-11 (IL-11Rα) is required specifically for normal establishment of the decidua. Females homozygous for a hypomorphic IL-11Rα allele are fertile and their blastocysts implant and elicit the decidual response. Because of reduced cell proliferation, however, only small deciduae form. Mutant deciduae degenerate progressively, and consequently embryo-derived trophoblast cells generate a network of trophoblast giant cells but fail to form a chorioallantoic placenta, indicating that the decidua is essential for normal fetoplacentation. IL-11Rα is expressed in the decidua as well as in numerous other tissues and cell types, including the ovary and lymphocytes. The differentiation state and proliferative responses of B and T-lymphocytes in mutant females were normal, and wild-type females carrying IL-11Rα mutant ovaries had normal deciduae, suggesting that the decidualization defects do not arise secondarily as a consequence of perturbed IL-11Rα signaling defects in lymphoid organs or in the ovary. Therefore, IL-11Rα signaling at the implantation site appears to be required for decidua development.     

EPO improves the proliferation and inhibits apoptosis of trophoblast and decidual stromal cells through activating STAT-5 and inactivating p38 signal in human early pregnancy

The erythropoietin (EPO) belongs to the family of angiogenic factors, which is regulated by Hypoxia-inducible factor- 1α (HIF-1α). As known, EPO are expressed in human villi and decidua, but the function is not clear. In this study, we investigated the expression and roles of HIF-1α, EPO and its receptor (EPOR) in the biological functions of trophoblast and decidual stromal cell (DSC) in human early pregnancy. The expression of EPO, EPOR and HIF-1α was evaluated in the villi and deciduas by RT-PCR and immunohistochemistry. Thereafter, we silenced HIF-1α expression in HTR-8/SVneo cell line and decidual stromal cells (DSCs). The effects of EPO on the proliferation and apoptosis of trophoblasts and DSCs, and activation of signal molecules were investigated by BrdU proliferation assay, flow cytometry and western blot, respectively. We have observed that the HIF-1α silence results in the lower expression of EPO in trophoblasts and DSCs. The anti-EPO neutralizing antibody can inactivate the phosphorylation of STAT5 and activate p38 of these cells in a dosage-dependent manner. Furthermore, the expressions of EPO, EPOR and HIF-1α in the villi and decidua from the unexplained miscarriage were significantly lower than that of the normal early pregnancy. This study suggests that HIF-1α may regulate the expression of EPO, which plays a favorable regulatory role in the proliferation and survival of human first-trimester trophoblast cells and DSCs via inactivating p38 and activating STAT5 in an autocrine manner, while the inadequate EPO expression at maternal-fetal interface may lead to pregnancy wastage in humans.     

Augmentation by transferrin of IL-2-inducible killer activity and perforin production of human CD8+ T cells.

The effects of human transferrin (Tf) on lymphokine (IL-2)-activated killer (LAK) induction from blood lymphocytes of healthy donors was examined. LAK cells were induced by 6-day incubation in medium with recombinant human IL-2 of lymphocytes, and their cytotoxic activity was assessed by measuring 51Cr release from NK-resistant Daudi cells. Tf alone did not induce any LAK activity, but in combination with IL-2, it augmented LAK induction dose- and time-dependently. This augmenting effect was completely abolished by pretreatment with anti-Tf antiserum. Tf augmented the proliferative response of lymphocytes to IL-2 and their expressions of receptors for IL-2 and Tf. CD8+ T cells were isolated from purified blood lymphocytes using antibody-bound magnetic beads. Addition of Tf to cultures of CD8+ cells resulted in significant augmentation of killer cell induction and perforin (PFP) production after 4 days stimulation with IL-2. These results indicate that Tf is important in generation of IL-2-inducible killer properties and PFP activity of human CD8+ T cells.     

Studies on T-Lineage Cells in Human Decidua of First Trimester Pregnancies

ABSTRACT: T-lineage cells in human decidua of early pregnancies were tested for surface markers, proliferative response, interleukin-2 (IL-2) production, and natural killer (NK) activity. T-lineage (CD2⁺) cells that were obtained from decidua by the use of E-rosette formation contained fewer CD3⁺ mature T cells and CD4⁺ cells than those from the peripheral blood of the same donors, while no differences were seen in the frequencies of CD8⁺ cells. P55 molecules of IL-2 receptor (IL-2R/p55, Tac antigen) were hardly detected on fresh decidual T-lineage cells, though approximately 20% were positive for HLA-DR. More than a half of decidual T-lineage cells expressed CD56 molecules on their surface and killed K562 cells, the prototype target of NK cells, while most of them were negative for CD16 and CD57. Upon stimulation with IL-2, decidual T-lineage cells demonstrated dose-dependent proliferative response. In addition, they were induced to produce high amounts of IL-2 by stimulation with mitogens but not with alloantigens. These results suggest that human decidua contains high numbers of CD2⁺3-CD16⁺56⁺ lymphocytes and that this population responds to IL-2, produces IL-2 and mediates NK activity.     

Decidual expression and localization of human surfactant protein SP-A and SP-D,and complement protein C1q

Surfactant proteins SP-A and SP-D, and complement protein C1q are soluble innate immune pattern recognizing molecules. SP-A, SP-D and C1q have an overall similar structure composed of an N-terminal triple-helical collagen region that is followed by a trimeric globular domain. While SP-A and SP-D belong to the collectin family (collagen containing lectin), C1q is the first recognition subcomponent of the classical pathway of the complement system. Recently, SP-A, SP-D and C1q have been considered to play important roles in early and late pregnancy. However, their expression in early human decidua has not been examined. Here, we investigated whether SP-A, SP-D and C1q are expressed within first trimester decidua in humans and their expression is associated with trophoblasts and decidual stromal cells. Decidual samples from women undergoing elective vaginal termination of pregnancy during first trimester were obtained from 25 subjects. Immunohistochemical studies using anti-human SP-A, anti-human SP-D and anti-human C1q antibodies were performed on decidual tissue sections along with anti-vimentin and cytokeratin-7 antibodies to identify stromal cells and trophoblasts. The expression was also examined by immunostaining and PCR using decidual and stromal cells. C1q expression was significantly higher when compared to SP-A and SP-D in the first trimester human decidua. Double immunostaining revealed that all stromal cells and trophoblasts expressed SP-A, SP-D and C1q, while only few invasive trophoblasts expressed C1q. Thus, expression of SP-A, SP-D and C1q in human decidua during first trimester suggests potential role of SP-A, SP-D and C1q during the early stages of pregnancy including implantation, trophoblast invasion and placental development.     

A novel in vitro model of trophoblast-mediated decidual blood vessel remodeling

In vivo the extravillous trophoblasts (EVTs) penetrate the decidua and the first third of the myometrium to remodel the uterine spiral arteries and achieve the high-flow, low-resistance circulation characteristic of the intervillous space of the term placenta. Much of our understanding of these processes comes from histologic analysis of placental bed biopsies, a limited tissue source and one that can provide only a snapshot of a dynamic process. To better characterize these cellular interactions, we have developed an in vitro co-culture system in which first trimester villous explants are cultured at low oxygen tension in contact with 2-mm(2) sections of decidua parietalis from the same patient. Hematoxylin eosin counterstaining of paraffin sections shows that EVT columns form at the tips of the placental villi and adhere and penetrate the decidual surface. The decidual blood vessels in the path of the EVT show morphologic disruption. Immunohistochemical analysis of the co-cultures using both an endothelial specific anti-CD31 and an anti-smooth muscle actin antibody show a disruption of the integrity of the vessel lining together with a complete loss of organized smooth muscle actin surrounding the blood vessels. In contrast control decidua samples in the absence of placental villi exhibit blood vessels with a complete endothelial lining and an organized muscular sheath. Using both an anti-cytokeratin-7 and anti-Cdx-2 antibody specific to trophoblasts, we show that these changes coincide with invasion of the vessels by endovascular trophoblasts and penetration of the decidua by interstitial EVTs. No EVTs were found in the control decidua. Thus we conclude that this in vitro model mimics the physiologic change observed in vivo during trophoblast invasion into maternal decidual tissues, and as such it may provide useful information concerning the interactions between EVTs and decidual cells and vessels during early gestation.     

Evidence for decidua--trophoblast interactions in early human pregnancy

Medium conditioned by decidual cells decreased the growth ofcultured BeWo choriocarcinoma cells. The degree of inhibitionwas dependent on the concentration of the conditioned mediumused, and suggested that maternal decidua might regulate thegrowth of the fetal placenta. Medium from BeWo cells and primarytrophoblast had the opposing effect and increased the growthof cultured decidual cells for up to 120 h of culture. Theseresults suggest that a regulatory loop to control placentaland decidual growth exists at the materno—fetal interface,and this may be an important factor in the development of adequateplacentation and the subsequent growth of the placenta duringpregnancy.     

Granulocyte colony stimulation factor (G-CSF) suppresses interleukin (IL)-12 and/or IL-2 induced interferon (IFN)-gamma production and cytotoxicity of decidual mononuclear cells

PROBLEM: The placenta is one of the few non-hematopoietic tissues to express granulocyte colony stimulation factor (G-CSF). Placental G-CSF production is considered to be one of the major causes of granulocytosis during pregnancy although its physiological role in pregnancy has not yet been examined. METHOD OF STUDY: The effects of G-CSF on interleukin (IL)-2 and/or IL-12 induced interferon (IFN)-gamma production of magnetic cell sorting (MACS) sorted decidual lymphocytes was examined by enzyme-linked immunosorbent spot-forming cell assay (ELISPOT). The effect of G-CSF on cytotoxicity of decidual lymphocytes against the choriocarcinoma cell line JEG-3 was examined by lactate dehydrogenase (LDH) release assay. RESULTS: As previously reported by us, IL-2 and/or IL-12 activated decidual mononuclear cells were capable of killing choriocarcinoma cells. We observed that G-CSF abolished IFN-gamma production and cytotoxicity of decidual mononuclear cells and MACS sorted CD56+ cells. CONCLUSIONS: In addition to its well-known trophic effects on hematopoiesis, our results suggest about new roles of G-CSF in reproductive immunology.     

HLA-G expression in extravillous trophoblasts is an intrinsic property of cell differentiation: a lesson learned from ectopic pregnancies

Human leukocyte antigen (HLA)-G is a major histocompatibility gene expressed almost exclusively in extravillous trophoblasts at the fetal-maternal interface. HLA-G may play a role in protecting the fetus from attack by the maternal natural killer cells. The extravillous trophoblasts invade the decidua and maternal spiral arteries. The factors which regulate the cell-specific expression of HLA-G are unknown. In this study we asked if HLA-G is expressed in extravillous trophoblasts that develop outside of their normal cellular environment, as in the case of ectopic pregnancies. Since all ectopic pregnancies implant in the absence of underlying decidua we also used a placenta accreta as an experimental control. We found that HLA-G mRNA and protein were expressed in the extravillous trophoblasts in the 13 ectopic specimens studied. In a case of placenta accreta (which develops without decidua basalis and is therefore adherent to the underlying myometrium), HLA-G mRNA and protein were also expressed. These results suggest that HLA-G expression is induced in a cell autonomous manner rather than determined by appropriate environmental cues.     

Changes in the pattern of expression of alkaline phosphatase in the mouse uterus and placenta during gestation

The development of the rodent chorio-allantoic placenta is a complicated process that results in the formation of a transport system capable of sustaining embryonic and fetal growth and development. Intimately linked to this process is alkaline phosphatase (AP), a cell-surface glycoprotein that possibly functions as a transport protein. In the present study, we have mapped the location of AP-expressing cells in the mouse utero-placental unit during the development of the chorio-allantoic placenta by use of enzyme histochemistry and in situ hybridization histochemistry. We found that at implantation the expression of the tissue non-specific AP (TNAP) gene is located exclusively in the decidua and that most of this decidual expression ceases as the placenta starts to form. One exception is a mesometrially located marginal zone of the decidua, which continues to express the TNAP gene until day 12 and the active protein until at least day 16. Trophoblasts of the chorion already express AP before the time of fusion with the ectoplacental cone, after which AP is expressed by trophoblasts of the resulting ectoplacental plate. AP expression in the mature chorio-allantoic placenta is localized in the placental labyrinth and spongy zones. In the latter zone, expression ceases on about day 14. Giant trophoblasts start to express AP on about day 10, with some cells still positive for AP at day 16. The yolk sac does not express AP at any developmental stage. The results show that AP expression during placental development is neither restricted to cells known to be involved in transport, nor expressed in all cells thought to be involved in this transport. This may indicate that AP is not merely a transport protein but has additional functions.     

Progesterone-induced blocking factor inhibits degranulation of natural killer cells.

PROBLEM: During the first trimester of pregnancy, nonclassical (CD3-, CD56+, CD16-, perforin [P]bright+) natural killer (NK) cells comprise the major decidual lymphocyte population. These cells, in spite of their high perforin content, exert a low cytolytic activity. Peripheral blood lymphocytes of healthy pregnant women produce progesterone-induced blocking factor (PIBF), which inhibits NK activity. PIBF-producing cells are likely to be present in decidua and might contribute to low decidual NK activity. METHOD OF STUDY: Decidual cells obtained from elective pregnancy termination were double labeled for CD56 and PIBF. We tested the effect of PIBF on perforin liberation by activated peripheral blood NK cells. RESULTS: Sixty percent of decidual lymphocytes were CD56 + and expressed PIBF at the same time. PIBF-treated and untreated peripheral blood NK cells were incubated with K-562 cells, and perforin content of target conjugated NK cells was detected with immunocytochemistry. PIBF treatment of peripheral blood lymphocytes significantly reduced lysis of K-562 cells. Among target bound lymphocytes in PIBF-treated samples, we found a significantly (P < 0.01) higher rate of P+ cells than in untreated samples. CONCLUSIONS: These data suggest that PIBF inhibits cytotoxicity of NK cells via a block of degranulation, and since decidual NK cells are PIBF+, it cannot be ruled out that this effect of PIBF contributes to low decidual NK activity.