Blockade of CD300A enhances the ability of human NK cells to lyse hematologic malignancies

Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(NK) cells targeting hematologic malignancies(HMs).Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine(PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients.Results: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS–CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an “exhausted” phenotype of intratumoral NK cells in patients with HMs or solid tumors.Conclusions: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.

Relation between Neurotransmitters and NK Cells in Adrenal and Breast Cancer

Purpose: Data on microarray gene expression The Gene Expression Omnibus (GEO) provided information on gene expression. Transcription GEO provided two profiles of human NK cells from breast and adrenal tumors (GSE179509 and GSE143383). Data processing and normalization The Dseq2 tool in the R programming language was used to standardize the raw data from GEO. The following analyses were carried out: fold change and P-value analysis, volcano plot, network analysis, GEPIA, and David pathway analysis. In this paper, using Venny software, we discovered 2 genes that are shared by neurotransmitters and NK cells in breast cancer and adrenal cancer. Between these genes and the pathways, they are a part of, we discovered a network. Pathway analysis revealed that these genes are mostly linked to the neurotransmitter and apoptotic pathways. In breast and adrenal tumors, the genes HRH1 and GABRD were discovered to be connected to NK cells. In response to breast and adrenal tumors, almost all of these genes are effective. It is thus postulated that the diagnosis of breast and adrenal cancer may be affected by the up-or down-regulation of these genes. Methods: Microarray gene expression data gene expression data was obtained from the Gene Expression Omnibus (GEO) Transcription 2 profile data of human NK cells from human breast and adrenal cancers were obtained from GEO (GSE179509 and GSE143383). Processing and normalization of data the raw data from GEO were normalized with the Dseq2 package in the R software. Fold change and P value analysis, Volcano plot, network analysis, GEPIA, and David pathway analysis were performed. Results: In this article, we found genes common to neurotransmitters with NK cells in adrenal cancer and breast cancer with Venny program, resulting in 2 genes. We identified a network between these genes and pathways they belong to. Pathway analysis showed that these genes are mostly associated with apoptosis and neurotransmitters pathway. Conclusion: HRH1 and GABRD genes were found to be associated with NK cells in breast and adrenal cancers. Almost all these genes are effective in response to breast and adrenal cancers. Therefore, it is hypothesized that downregulation or upregulation of these genes may affect breast and adrenal cancer diagnosis.

Internalization of NK cells into tumor cells requires ezrin and leads to programmed cell-in-cell death

Cytotoxic lymphocytes are key players in the orchestration of immune response and elimination of defective cells. We have previously reported that natural killer （NK） cells enter target tumor ceils, leading to either target cell death or self-destruction within tumor cells. However, it has remained elusive as to the fate of NK cells after internalization and whether the heterotypic cell-in-cell process is different from that of the homotypic cell-in-cell event recently named entosis. Here, we show that NK cells undergo a cell-in-cell process with the ultimate fate of apoptosis within tumor cells and reveal that the internalization process requires the actin cytoskeletal regulator, ezrin. To visualize how NK cells enter into tumor cells, we carried out real-time dual color imaging analyses of NK cell internalization into tumor cells. Surprisingly, most NK cells commit to programmed cell death after their entry into tumor cells, which is distinctively different from entosis observed in the homotypic cell-in-cell process. The apoptotic cell death of the internalized NK cells was evident by activation of caspase 3 and DNA fragmentation. Furthermore, NK cell death after internalization is attenuated by the caspase inhibitor, Z-VAD-FMK, confirming apoptosis as the mode of NK cell death within tumor cells. To determine protein factors essential for the entry of NK cells into tumor cells, we car- ried out siRNA-based knockdown analysis and discovered a critical role of ezrin in NK cell internalization. Impor- tantly, PKA-mediated phosphorylation of ezrin promotes the NK cell internalization process. Our findings suggest a novel regulatory mechanism by which ezrin governs NK cell internalization into tumor cells.

Study on T lymphocyte subsets and NK cells in patients with Graves' disease combined with type 2 diabetes

Objective To investigate changes in T lymphocyte subsets and NK cells in patients with simple Graves’ disease(GD)and Graves’ disease combined with type 2 diabetes mellitus(GD/T2DM).Methods Fifteen cases of GD/T2DM were selected from our hospital from November 2001 to November 2004.Before and after therapy thyroid function,thyroglobulin antibody(TGA),thyroid microsomal antibody(TMA)and blood glucose level were measured,and T lymphocyte subsets(CD3,CD4,CD8,CD4/CD8)and NK cells(CD56)were measured by immunofluorescence double labeling monoclonal antibody and flow cytometry,respectively.At the same time,comparison was made with simple GD(15 cases),T2DM(15 cases)and healthy control(20 cases).Results Before therapy,CD4/CD8,CD4 and NK cells in GD/T2DM were less than normal,and there was no significant difference in comparison with simple GD(P<0.05).In T2DM group,only CD4/CD8 and CD4 were less than those of healthy controls(P<0.05).When thyroid function recovered after 1 to 3 months of methimazole treatment in both GD/T2DM and simple GD groups,various indexes recovered,which were more obvious in simple GD.Conclusion Immune hypofunction of GD may be the key to the immune abnormality of GD/T2DM,which is more significant than that of simple GD or T2DM.The recovery of thyroid function and immune abnormality is not consistent,and the recovery of GD is more significant than that of GD/T2DM.

Research on the effects of CD137 signaling on the function of CD3^-CD56^+NK cells

Objective： To investigate the effects of CD137 signaling on the regulation of CD3-CD56＋NK cells function. Methods： CD3 CD56＋NK cells were treated with CD137 mAb or mouse IgG 1 isotype control to study the effects of CD 137 signaling on the function of CD3-CD56＋NK cells. Cytotoxicity was measured by LDH activity in the supernatants of cell cultures; NKG2D and LFA-I expression on CD3-CD56＋NK cells were analyzed by flow cytometry. Results： CD137 was expressed on activated CD3-CD56＋NK cells. The CD137 mAb enhanced the ability of CDB-CD56＋NK cells to kill lung cancer cells（A549）; Further studies revealed that the expression of NKG2D and LFA-1 was significantly increased in activated cells, and blockade of NKG2D and LFA-1 dramatically attenuated CD3CD56＋NK cytolysis of A549 cancer cells. Conclusion： CD 137 signaling increases the ability of CD3-CD56＋NK cells to kill cancer cells via up- regulating the expression of NKG2D and LFA-1.

Im m unoregulatory Effects of Triptergium W ilfordii Hook at Antifertility Dose on Splenic NK Cells Activityin Male Mice

Effects of Tripterypium Wilfordii Hook f (TWH) on sperm atozoa in the epi- didym is and splenic NK cells activity in m ale m ice w ere observed using MTT assay and silver impregnation m ethods. The results show ed that the density, viability and m otility of the epididym alsperm atozoa in the experim entalgroupstreated w ith TWH w ere m ore significantly reduced than those in the controlgroup (P< 0.01). The head sw elling, head separation from tailin the groups treated w ith TWH w ere observed. The inhibition of splenicNK cellsactivity in m iceby TWH w asdose-dependent. Inhi- bition by TⅡand TWH athigh dose on the NK cells activity w as significant (P< 0.01 and P< 0.05), w hileinhibitory effectsof TWH atinterm ediateand low doseson the NK cells activity w ere notobserved (P> 0.05). Itw as concluded thatTWH at low er antifertility dose did not significantly inhibit the splenic NK cells activity. It m ightbe usefulforevaluating thetherapeuticeffectsof TWH in futureclinicalprac- tice.

Studies on Activity of NK Cells in Preeclampsia Patients

The activity of the NK cells in patients with preeclampsia was studied to investigate the pathogenesis of preeclampsia. By using MTT and 51Cr releasing technique, the proliferation and killing ability of the NK cells in maternal and umbilical blood from preeclampsia patients (n=18) and normal third trimester pregnant women (n=18) were detected. The NK-92 cell line was as the positive control. The results showed that the NK cell counts of umbilical blood in preeclampsia patients and normal third trimester pregnant women were significantly greater than those of maternal blood (both P<0.05). Compared with that in normal third trimester pregnant women, the proliferative ability of the NK cells in preeclampsia patients was apparently increased (P<0.05). Compared with that in maternal blood, the proliferative ability of the NK cells in umbilical blood from both preeclampsia patients and normal third trimester pregnant women was dramatically increased. The killing ability of the NK cells in preeclampsia patients was significantly higher than that in normal third trimester pregnant women (P <0.05). It was suggested that both number and function of the NK cells in preeclampsia women were increased, and that in umbilical blood was greater than that in maternal blood, speculating that the function of the NK cells may affect the maintenance of the maternal and fetal immune tolerance during pregnancy.

Effect of Mg^(2+)level on the functions of CD8^(+)T lymphocytes and NK cells in patients with COVID-19

Objective:To investigate the changes of Mg^(2+) levels in serum and peripheral blood mononuclear cells(PBMCs)of patients with COVID-19 and its effects on the functions of CD8^(+)T lymphocytes and NK cells.Methods:A total of 165 COVID-19 patients hospitalized in Ezhou Central Hospital from January 20 to February 20,2020 were divided into mild/common group(98 cases)and severe/critical group(67 cases).At the same time,34 healthy persons were selected as the control group.Peripheral blood was collected and PBMCs were isolated,the level of Mg^(2+) in serum and PBMCs was detected.The subsets of CD8^(+)T lymphocytes and NK cell and the expression levels of their surface inhibitory molecular PD-1 and activator molecular NKG2D were detected by flow cytometry.The correlation between Mg^(2+) concentration and the expression levels of PD-1 and NKG2D was also analyzed.Results:Compared with the control group,the concentration of Mg^(2+) in serum and PBMCs,the counts of CD8^(+)T lymphocytes and NK cell in patients with mild/common and severe/critical groups were significantly reduced(P<0.05),while the expression level of surface inhibitory molecular PD-1 were significantly increased(P<0.05),while the expression level of the activation molecule NKG2D were significantly decreased(P<0.05).However,the changes of the above indicators in patients with severe/critical group were greater than those in the mild/common group(P<0.05).In addition,the Mg^(2+) concentration in COVID-19 patients was negatively correlated with the expression level of PD-1 on CD8^(+)T lymphocytes and NK cells(P<0.05),and positively correlated with the expression levels of NKG2D(P<0.05).Conclusion:The concentration of Mg^(2+) in the serum and PBMCs of COVID-19 patients is significantly reduced,which may cause the function of CD8^(+)T lymphocytes and NK cells to be inhibited.

Interleukin-15 Promotes the Commitment of Cord Blood CD34^+ Stem Cells into NK Cells

To explore the effect of rhIL-15 on CB-CD34 + stem cells committing to NK cells, CD34 + stem cells were obtained from cord blood (CB) by magnetic-assisted cell sorting (MACS) method. CD3, CD16 and CD56 molecules expressed on cell surface were detected by flow cytometer. MTT method was used to test the cytotoxicity of NK cells. The results were that stem cell factor (SCF) alone has no effect on CD34 + stem cells. IL-15 stimulated CD34 + stem cells commit to NK cells, and SCF showed strong synergistic effect with IL-15. It was concluded that IL-15 and SCF played different roles during NK cell development, IL-15 promoted CD34 + stem cells differentiate to NK cell precursor and SCF improved the effects of IL-15 on NK cell differentiation.

Decreased LDHB expression in breast tumor cells causes NK cell activation and promotes tumor progression

Objective: Abnormal metabolism is the underlying reason for breast cancer progression. Decreased lactate dehydrogenase B(LDHB) has been detected in breast cancer but the function of LDHB remains unknown.Methods: Western blot was used to analyze LDHB expression in breast cancer cells. The impact of LDHB on tumor cell migration and invasion was determined using Transwell assays, wound healing assays, and a mouse lung metastasis model. Subcutaneous tumor formation, a natural killer(NK) cell cytotoxicity assay, and flow cytometry evaluated NK cell activation. Immunofluorescence and quantitative real-time PCR detected NK cell activation markers. Kaplan-Meier analysis evaluated the effect of immune cell infiltration on prognosis. Single-sample gene set enrichment analysis determined NK cell activation scores. A support vector machine predicted the role of LDHB in NK cell activation.Results: In this study we showed that LDHB inhibits the breast cancer cell metastasis and orchestrates metabolic reprogramming within tumor cells. Our results revealed that LDHB-mediated lactic acid clearance in breast cancer cells triggers NK cell activation within the tumor microenvironment. Our findings, which were confirmed in a murine model, demonstrated that LDHB in tumor cells promotes NK cell activation and ultimately results in the eradication of malignant cells. Clinically, our study further validated that LDHB affects immune cell infiltration and function. Specifically, its expression has been linked to enhanced NK cell-mediated cytotoxicity and improved patient survival. Furthermore, we identified LDHB expression in tumors as an important predictor of NK cell activation, with strong predictive ability in some cancers.Conclusions: Our results suggest that LDHB is a promising target for activating the tumor immune microenvironment in breast cancer, where LDHB-associated lactic acid clearance leads to increased NK cell activity. This study highlights the critical role of LDHB in regulating immune responses and its potential as a therapeutic target for breast cancer.

Depletion but Activation of CD56dimCD16+ NK Cells in Acute Infection with Severe Fever with Thrombocytopenia Syndrome Virus

Severe fever with thrombocytopenia syndrome(SFTS)is an emerging infectious disease with high mortality(12%–30%).The mechanism by which the SFTS bunyavirus(SFTSV)causes severe illness remains unclear.To evaluate the phenotypic and functional characteristics of the NK cell subsets in SFTS patients,twenty-nine SFTS patients were sequentially sampled from admission until recovery.Phenotypic and functional characteristics of NK cell subsets in circulating blood were analysed via flow cytometry.Then,correlations between NK cell subset frequencies and the SFTS index(SFTSI)were evaluated in all SFTS patients(15 mild,14 severe)upon admission.The frequencies of CD56dimCD16+NK cells were greatly decreased in early SFTSV infection and were negatively correlated with disease severity.Additionally,higher Ki-67 and granzyme B expression and relatively lower NKG2 A expression in CD56dimCD16+NK cells were observed in acute infection.Moreover,the effector function of CD56dimNK cells was increased in the acute phase compared with the recovery phase in nine severe SFTS patients.Additionally,interleukin(IL)-15,interferon(IFN)-a,IL-18 and IFN-c secretion was markedly increased during early infection.Collectively,despite depletion of CD56dimCD16+NK cells,activation and functional enhancement of CD56dimCD16+NK cells were still observed,suggesting their involvement in defence against early SFTSV infection.

Human NK cells: surface receptors, inhibitory checkpoints, and translational applications

NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis.The regulation/induction of NK cell function is mediated by an array of activating or inhibitory surface receptors.In humans,major activating receptors involved in target cell killing are the natural cytotoxicity receptors(NCRs)and NKG2D.Activating receptors recognize ligands that are overexpressed or expressed de novo upon cell stress,viral infection,or tumor transformation.The HLA-class I-specific inhibitory receptors,including KIRs recognizing HLA-class I allotypic determinants and CD94/NKG2A recognizing the class-Ib HLA-E,constitute a fail-safe mechanism to avoid unwanted NK-mediated damage to healthy cells.Other receptors such as PD-1,primarily expressed by activated T lymphocytes,are important inhibitory checkpoints of immune responses that ensure T-cell tolerance.PD-1 also may be expressed by NK cells in cancer patients.Since PD-1 ligand(PD-L1)may be expressed by different tumors,PD-1/PD-L1 interactions inactivate both T and NK cells.Thus,the reliable evaluation of PD-L1 expression in tumors has become a major issue to select patients who may benefit from therapy with mAbs disrupting PD-1/PD-L1 interactions.Recently,NKG2A was revealed to be an important checkpoint controlling both NK and T-cell activation.Since most tumors express HLA-E,mAbs targeting NKG2A has been used alone or in combination with other therapeutic mAbs targeting PD-1 or tumor antigens(e.g.,EGFR),with encouraging results.The translational value of NK cells and their receptors is evidenced by the extraordinary therapeutic success of haploidentical HSCT to cure otherwise fatal high-risk leukemias.

Trophoblast-derived CXCL16 induces M2 macrophage polarization that in turn inactivates NK cells at the maternal–fetal interface

Decidual macrophages (dMΦ) are distinct from the conventional macrophages present in other tissues and express M2macrophage markers, but the molecular mechanisms of formation and the roles of M2 MΦ during pregnancy have not beencompletely elucidated. The crosstalk between decidual natural killer cells (dNK) and dMΦ plays an important role in themaintenance of maternal–fetal immune tolerance. Here, CXCL16 derived from first-trimester trophoblast cells induces thepolarization of human M2 macrophages. The M2 MΦ polarized by CXCL16 exhibit decreased interleukin-15 production, whichfacilitates the inactivation of NK cells. The cytotoxicity of NK cells is attenuated by the CXCL16-polarized M2 MΦ. The data shown inthe present study provide evidence to support the hypothesis that CXCL16 secreted by trophoblast cells is a key molecule involvedin decidual M2 MΦ polarization, which in turn regulates the killing ability of NK cells, thereby contributing to the homeostatic andimmune-tolerant milieu required for successful fetal development.

Human fused NKG2D-IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells

Interleukin （IL）-15 plays an important role in natural killer （NK） and CD8＋ T-cell proliferation and function and is more effective than IL-2 for tumor immunotherapy. The trans-presentation of IL-15 by neighboring cells is more effective for NK cell activation than its soluble IL-15. In this study, the fusion protein dsNKG2D-IL-15, which consisted of two identical extracellular domains of human NKG2D coupled to human IL-15 via a linker, was engineered in Escherichia coll. DsNKG2D-IL- 15 could efficiently bind to major histocompatibility complex class I chain-related protein A （MICA） of human tumor cells with the two NKG2D domains and trans-present IL-15 to NK or CD8＋ T cells. We transplanted human gastric cancer （SGC-7901） cells into nude mice and mouse melanoma cells with ectopic expression of MICA （B 16BL6-MICA） into C57BL/6 mice. Then, we studied the anti-tumor effects mediated by dsNKG2D-IL-15 in the two xenografted tumor models. Human dsNKG2D-IL-15 exhibited higher efficiency than IL-15 in suppressing gastric cancer growth. Exogenous human dsNKG2D-IL-15 was centrally distributed in the mouse tumor tissues based on in vivo live imaging. The frequencies of human CD56＋ cells infiltrated into the tumor tissues following the injection of peripheral blood mononuclear cells into nude mice bearing human gastric cancer were significantly increased by human dsNKG2D-I L- 15 treatment. Human dsNKG2 D-I L- 15 also delayed the growth of transplanted melanoma （B 16BL6- MICA） by activating and recruiting mouse NK and CD8＋ T cells. The anti-melanoma effect of human dsNKG2D-IL-15 in C57BL/6 mice was mostly decreased by the in vivo depletion of mouse NK cells. These data highlight the potential use of human dsNKG2D-IL-15 for tumor therapy.

CD49a^(+)CD49b^(+) NK cells induced by viral infection reflect an activated state of conventional NK cells

Natural killer(NK) cells are important innate effectors that play a pivotal role in the defense against tumors and infections and participate in regulating adaptive immunity. Recent studies have revealed phenotypic and functional heterogeneity of NK cells.Here, using murine models of acute and chronic lymphocytic choriomeningitis virus infection, we observed that a CD49a^(+)CD49b^(+) NK cell subset emerged in the liver and other tissues, and underwent vigorous expansion following viral infection,before progressively decreasing in cell number. These viral infection-induced CD49a^(+)CD49b^(+) NK cells displayed an activated and mature phenotype. Moreover, compared with liver-resident NK cells and conventional NK(cNK) cells, CD49a^(+)CD49b^(+) NK cells showed increased functional competence, as evidenced by higher amounts of IFN-γ production and stronger cytotoxic capabilities during viral infection. Generation of these CD49a^(+)CD49b^(+) NK cells was shown to be independent of the T-bet transcription factor. Adoptive transfer experiments revealed that c NK cells could convert into CD49a^(+)CD49b^(+) NK cells following viral infection. Collectively, these results suggest that viral infection-induced CD49a^(+)CD49b^(+) NK cells represent a transiently activated state of cNK cells.

Quantities and function of NK cells in patients with positive BMMNC-Coombs test and cytopenia

Objective To test NK cell quantities and function in patients with positive BMMNC-Coombs test(CBCPC)and cytopenia and to explore how NK cell participate in the progress of this disease.Methods The percentage of CD3-CD56+NK cell in peripheral blood lymphocytes,the expression of activating receptor(NKG2D,NKp46,NKp44),inhibitory receptor(CD158a,CD158b),per-

Memory NK cells： why do they reside in the liver？

Immune memory is the hallmark of adaptive immunity. However, recent studies have shown that natural killer （NK） cells, key components of the innate immune system, also mediate memory responses in mice and humans. Strikingly, memory NK cells were liver-resident in some models, raising the question as to whether the liver is a special organ for the acquisition of NK cell memory. Here, we review the characteristics of N K cell memory by summarizing recent progress and discuss how the liver may generate both the initiation and the recall phase of memory. We propose that the liver may have unique precursors for memory NK cells, which are developmentally distinct from NK cells derived from bone marrow.

Leptin Signaling Protects NK Cells from Apoptosis During Development in Mouse Bone Marrow

Increasing evidence indicates a role of leptin in immune response, but it remains largely unclear whether leptin signaling is involved in regulating NK cell development in the bone marrow （BM）. In this study, we have characterized NK cell differentiation and maturation in the BM of leptin-receptor deficient db/db mice at a prediabetic stage. Although the BM cellularity was similar to the control value, the total number of NK cells was severely reduced in mutant mice. Flow cytometric analysis of db/db BM cells revealed significantly decreased frequencies of developing NK cells at various stages of differentiation. BM db/db NK cells displayed markedly increased apoptosis but maintained normal cell cycling status and proliferative capacity. Moreover, recombinant leptin could significantly enhance the survival of NK cells from wild-type mice in cultures. Further examination on NK cell functional activity showed that db/db NK cells exhibited normal intrinsic cytotoxicity with significantly increased IL-10 production. Taken together, our findings suggest that leptin signaling regulates NK cell development via enhancing the survival of immature NK cells in mouse BM.

IP-10 and fractalkine induce cytotoxic phenotype of murine NK cells

We characterized the murine NK cell subsets of the tumor microenvironment （TME） with low expressions of CD16 and NKG2D and investigated the chemokines that deter CD 16~~w NKG2Dl^w subsets. Our results demonstrated the activation of primary and KY- 1 NK cell by ligands and found that exogenous CXCL10/interferon-gamma-induced protein 10 （IP-10） and fractalkine （FKN） can up-regulate the expression of CD 16 and NKG2D. Moreover, both IP-10 and FKN are shown to facilitate migration, adhesion and cyto- toxicity of NK cell subsets of the TME, due to the up-regu- lated CD16 and NKG2D. Overall, our data provide a new path by which to enhance murine NK cell cytotoxic potential and improve the quality of NK cells of the TME.

Decidual Natural Killer Cells Are Essential for a Successful Pregnancy (Review)

Pregnancy is a complex physiological process involving several interconnected systems. Many researchers were concerned that the formation of a fetus with different genetic components may contradict the normal state of immunity, which attempts to reject and fight foreign bodies. This piqued the interest of biologists and immunologists, who set out to discover the immune system’s composition and mode of response in the uterus. According to several studies, natural killer (NK) cells are present in a significant percentage that differs from what is seen in peripheral blood. As a result, several scientific studies have been conducted on uterine NK cells, investigating their types, characteristics, receptors, secretions, and interactions with the surrounding environment. Research has also indicated the capacity of uterine NK cells to strike a balance between eradicating uterine infections and effectively contributing to different phases of pregnancy. Various studies have shown that NK cell activity is intimately related to the success or failure of pregnancy. In this review, we describe the uterine NK cell subtypes;decidual (dNK) cells and endometrial NK cells (eNK) cells and their important role during different phases of pregnancy.