Frequent CD7 Antigen Loss in Aggressive Natural Killer-Cell Leukemia Can Be a Useful Diagnostic Marker.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2400-2400
Author(s):  
Sun-Hee Kim ◽  
Eun-Hyung Yoo ◽  
Hee-Jin Kim ◽  
Won Seog Kim
Keyword(s):  
Bone Marrow ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
Diagnostic Marker ◽  
Clinical Course ◽  
Killer Cell ◽  
Cell Leukemia ◽  
Laboratory Findings ◽  
Antigen Loss

Abstract Aggressive natural killer-cell leukemia (ANKL) is a rare neoplasm characterized by systemic proliferation of NK cells with rapidly progressive clinical course and fatal outcome. Because of the aggressive clinical course, rapid and accurate diagnosis of ANKL is critical. However, the differential diagnosis of NK cell lymphoproliferative disorders including hemophagocytic lymphohistiocytosis is still challenging in the absence of a distinct diagnostic hallmark. Furthermore, cases with a low burden of malignant cell polpuation makes it more difficult. To find any diagnostic markers in ANKL, we analyzed clinical data and laboratory findings from bone marrow studies in Korean patients with bone marrow involvement of ANKL. From January 2000 to July 2007, a total of 20 cases were diagnosed with ANKL based on morphologic and immunophenotypic findings from bone marrow studies. The leukemic cells were surface CD3–CD16/56+ large granular lymphocytes with pale or lightly basophilic cytoplasm containing azurophilic granules. We retrospectively analyzed clinical features and laboratory findings including complete blood count (CBC), Epstein-Barr virus (EBV) status, serum lactate dehydrogenase (LDH) level, immunophenotype, and cytogenetic results from medical records. There were 6 (30%) women and 14 (70%) men with a median age of 44 years (range, 2–70 years). Hepatomegaly (70%), splenomegaly (60%), and lymphadenopathy (30%) were frequently observed. Peripheral blood counts were variable; anemia (hemoglobin <10g/dL) was predominant in 14 patients and thrombocytopenia (platelet <100×109/L) in 16. The proportion of leukemic NK cells ranged 3∼70%. EBV was detected in 15 of 18 cases (83%) by EBV in situ hybridization or EBV quantitative PCR. Cytogenetic studies were performed in 18 cases, and karyotypic abnormalities were observed in 50% (9/18). There were no recurrent cytogenetic abnormalities, except 6q abnormalities observed in 4 cases (4/18, 22%). The immunophenotype of the leukemic NK cells by flow cytometry was cytoplasmic CD3+, surface CD3−, CD16/56+, CD2+, and CD5−. Most cases were CD4− (13/16, 81%) and CD8− (11/14, 79%). Of note, loss of CD7 antigen was observed in 10 patients (10/20; 50%) (normal NK cells: CD2+, CD7+, and CD5−). There were no significant differences in clinical or laboratory parameters between the CD7+ and CD7− groups. All three cases with deletion of 6q revealed absent expression of CD7. When the CD7 loss was combined with cytogenetic abnormalities, clonal markers could be identified in 75% of ANKL cases. We observed frequent CD7 antigen loss in our series of Korean patients with ANKL. This characteristic immunophenotypic finding can provide a reliable and timely information as a diagnostic marker in ANKL along with cytogenetic findings. Therefore, immunophenotypic analysis of the expression of CD7 should be included in the diagnostic workup of NK cell neoplasms.

Frequent CD7 Antigen Loss in Aggressive Natural Killer-Cell Leukemia: A Useful Diagnostic Marker

2009 ◽  
Vol 29 (6) ◽  
pp. 491-496 ◽  
Author(s):  
Eun-Hyung Yoo ◽  
Hee-Jin Kim ◽  
Seung-Tae Lee ◽  
Won-Seog Kim ◽  
Sun-Hee Kim
Keyword(s):  
Natural Killer Cell ◽  
Natural Killer ◽  
Diagnostic Marker ◽  
Killer Cell ◽  
Cell Leukemia ◽  
Antigen Loss

scholarly journals Hepatic Niche Leads to Aggressive Natural Killer Cell Leukemia Proliferation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3309-3309
Author(s):  
Kazuaki Kameda ◽  
Yuji Miyatake ◽  
Yoshinobu Kanda ◽  
Ai Kotani
Keyword(s):  
Bone Marrow ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Rna Sequencing ◽  
Research Funding ◽  
Killer Cell ◽  
Cell Leukemia

Abstract Aggressive natural killer cell leukemia (ANKL) is a rare form of natural killer (NK)-cell neoplasm with median survival of less than 2 months. Recently, the genomic mutation analysis using tumor cells reveled that the mutational profile of ANKL was similar to that of extranodal NK / T-cell lymphoma, which has relatively better prognosis than ANKL, explaining no causative mutations with a dismal prognosis. Here, using patient-derived xenograft model (PDX) mouse, we show that hepatic niche plays an important role in the ANKL biology. We established PDX mouse by intravenously injecting ANKL cells derived from patient peripheral blood or bone marrow samples to immunocompromised mice, which enables comprehensive analysis for tumor cells as well as tumor microenvironment. In total, we obtained four PDX strains derived from different patients. Time series pathological and flowcytometric analyses revealed that the ANKL cells initially engrafted and proliferated in sinusoidal or peri-portal area of the liver. This sinusoid or peri-portal distribution of ANKL in the liver was also confirmed with the patient liver specimen. To further determine the feature of ANKL in the liver, we selected liver or spleen tropic cells by serial adaptive transfer from each organ to the next mice. The liver-tropic ANKL cells proliferated more rapidly than splenic ANKL cells, which was evident by the significantly shorter survival of PDX mice injected liver-tropic cells (Figure). We performed RNA-sequencing using liver-tropic ANKL cells, spleen-tropic ANKL cells and NK-cells derived from healthy donors. These three types of cells showed distinct populations in principal component analysis. To further clarify the interaction between ANKL and liver niche, we performed additional RNA sequencing using total liver of mouse with or without bearing leukemic cells. In the cell-cell interaction analysis, we used two computational methods, mixed-species RNA-seq (Komura, et al. BMC Genomics 2016), which can distinguish transcripts derived from human (cancer) with mouse (non-cancer niche cells), and NicheNet (Browaeys, et al. Nat Methods 2020), which is a computational algorithm to model intercellular communication by linking ligands to target genes. These two methods allowed us to investigate the interaction between liver niche ligands and ANKL receptors. Among the listed ligand-receptor interactions, we focused on the macrophage migration inhibitory factor (MIF) and its receptor, CD74 axis. While CD74 was upregulated in ANKL cells compared with normal NK cells, MIF was highly expressed in the liver mainly liver sinusoid and Kupffer cells. Although we failed to culture primary ANKL cells in vitro, ANKL cells treated with MIF showed improved viability in vitro compared with untreated cells. Deletion of CD74 on the ANKL cells using CRISPR-Cas9 system attenuated the tumor formation in the liver as well as in bone marrow and spleen of PDX mouse compared with the wild type ANKL cells. These findings highlight that the liver, non-canonical hematopoietic organ in adults, is a principal niche where the liver specific components are required for survival and proliferation of ANKL cells. MIF-CD74 axis might play an important role in the communication between ANKL and hepatic niche. Figure 1 Figure 1. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding; Sanofi: Research Funding; MSD: Honoraria.

scholarly journals Aggressive natural killer cell leukemia in an adult with establishment of an NK cell line

Blood ◽  
1986 ◽  
Vol 67 (4) ◽  
pp. 925-930 ◽  
Author(s):  
LA Fernandez ◽  
B Pope ◽  
C Lee ◽  
E Zayed
Keyword(s):  
Platelet Count ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Line ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Killer Cell ◽  
Chromosome 1 ◽  
Cell Leukemia ◽  
Wbc Count

Abstract There have been many reports of cases in which chronic increases in the numbers of natural killer (NK) cells have been reported. Whether this is reactive or neoplastic in nature has been debated. We report the first case of an aggressive NK cell leukemia in an adult with establishment of an NK cell line. A 70-year-old man had two spontaneous episodes of jejunal perforation and one month later developed a severe febrile illness with moderate splenomegaly. Hemoglobin was 13.1 g/L, and WBC count was 1.8 X 10(9)/L with 2% large granular lymphocytes (LGLs). Platelet count was 143 X 10(9)/L; prothrombin time (PT) and partial thromboplastin time (PTT) were normal. Bone marrow was infiltrated with 25% to 30% LGLs; serum lysozyme was normal. Serum LDH was initially 1,191 U/L and rose to 6,408 (normal 240 to 525 U/L). Ten days later, the WBC count increased to 99.9 X 10(9)/L with 70% LGL cells; the PT and PTT increased, and the platelet count dropped. No bacterial or viral cause of fever was identified. The cells from peripheral blood were LGLs that stained positively for acid phosphatase. All of the LGLs reacted with a monoclonal antibody reactive with NK cells (LEU-11b). Functionally, the patient's peripheral blood mononuclear cells (PBMs) demonstrated 100 times more lytic activity against K562 tumor cell lines than did normal PBMs. The patient's PBMs were propagated in vitro. The cultured cells showed the morphological, cytochemical, immunological, and functional characteristics of NK cells. In addition, partial trisomy involving chromosome 1 q with duplication in regions of q21 through q31 was observed in all metaphases analyzed. The extra chromosome 1q with duplication in regions q21 through q31 was translocated to the p- terminal of chromosome 5. One percent to 5% of normal PBMs comprise NK cells; in most cases, leukemias arise from normal phenotypic counterparts. This case demonstrated that aggressive NK cell leukemia may occur in adults. In addition, the chromosomal abnormalities suggest that this is not a reactive process but a malignancy.

scholarly journals A research-driven approach to the identification of novel natural killer cell deficiencies affecting cytotoxic function

Blood ◽  
2020 ◽  
Vol 135 (9) ◽  
pp. 629-637
Author(s):  
Michael T. Lam ◽  
Emily M. Mace ◽  
Jordan S. Orange
Keyword(s):  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Impact Testing ◽  
Primary Immune Deficiency ◽  
Cell Cytotoxicity ◽  
Nk Cell Cytotoxicity

Abstract Natural killer cell deficiencies (NKDs) are an emerging phenotypic subtype of primary immune deficiency. NK cells provide a defense against virally infected cells using a variety of cytotoxic mechanisms, and patients who have defective NK cell development or function can present with atypical, recurrent, or severe herpesviral infections. The current pipeline for investigating NKDs involves the acquisition and clinical assessment of patients with a suspected NKD followed by subsequent in silico, in vitro, and in vivo laboratory research. Evaluation involves initially quantifying NK cells and measuring NK cell cytotoxicity and expression of certain NK cell receptors involved in NK cell development and function. Subsequent studies using genomic methods to identify the potential causative variant are conducted along with variant impact testing to make genotype-phenotype connections. Identification of novel genes contributing to the NKD phenotype can also be facilitated by applying the expanding knowledge of NK cell biology. In this review, we discuss how NKDs that affect NK cell cytotoxicity can be approached in the clinic and laboratory for the discovery of novel gene variants.

Adrenergic β1- and β1+2-receptor blockade suppress the natural killer cell response to head-up tilt in humans

1997 ◽  
Vol 83 (5) ◽  
pp. 1492-1498 ◽  
Author(s):  
M. Klokker ◽  
N. H. Secher ◽  
P. Madsen ◽  
M. Pedersen ◽  
B. K. Pedersen
Keyword(s):  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Response ◽  
Nk Cell ◽  
Killer Cell ◽  
Saline Control ◽  
Receptor Blockade ◽  
Natural Killer Cell Response ◽  
Head Up Tilt

Klokker, M., N. H. Secher, P. Madsen, M. Pedersen, and B. K. Pedersen. Adrenergic β1- and β1+2-receptor blockade suppress the natural killer cell response to head-up tilt in humans. J. Appl. Physiol. 83(5): 1492–1498, 1997.—To evaluate stress-induced changes in blood leukocytes with emphasis on the natural killer (NK) cells, eight male volunteers were followed during three trials of head-up tilt with adrenergic β1- (metoprolol) and β1+2- (propranolol) blockade and with saline (control) infusions. The β1- and β1+2-receptor blockade did not affect the appearance of presyncopal symptoms, but the head-up tilt induced a transient lymphocytosis that was abolished by β1+2-receptor blockade but not by β1-receptor blockade. Head-up tilt also resulted in delayed neutrophilia, which was insensitive to β-receptor blockade. Lymphocyte subset analysis revealed that the head-up tilt resulted in a twofold increase in the percentage and absolute number of CD3−/CD16+and CD3−/CD56+NK cells in peripheral blood and that this increase was partially blocked by metoprolol and abolished by propranolol. The NK cell activity on a per NK cell basis did not change during head-up tilt, indicating that the cytotoxic capability of NK cells recruited to circulation is unchanged. The data suggest that the head-up tilt-induced lymphocytosis was due mainly to CD16+and CD56+NK cells and that their recruitment to the blood was inhibited by β1- and especially β1+2-receptor blockade. Thus stress-induced recruitment of lymphocytes, and of NK cells in particular, is mediated by epinephrine through activation of β-receptors on the lymphocytes.

scholarly journals Natural killer cells suppress human erythroid stem cell proliferation in vitro

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 260-269 ◽  
Author(s):  
KF Mangan ◽  
ME Hartnett ◽  
SA Matis ◽  
A Winkelstein ◽  
T Abo
Keyword(s):  
Stem Cell ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Natural Killer Cell ◽  
Percoll Density Gradient Centrifugation

Abstract To determine the role of natural killer (NK) cells in the regulation of human erythropoiesis, we studied the effects of NK-enriched cell populations on the in vitro proliferation of erythroid stem cells at three different levels of maturation (day 14 blood BFU-E, day 5–6 marrow CFU-E, and day 10–12 marrow BFU-E). NK cells were enriched from blood by Percoll density gradient centrifugation and by fluorescence- activated cell sorting (FACS), using the human natural killer cell monoclonal antibody, HNK-1. The isolated enriched fractions were cocultured with autologous nonadherent marrow cells or blood null cells and erythropoietin in a methylcellulose erythroid culture system. Cells from low-density Percoll fractions (NK-enriched cells) were predominantly large granular lymphocytes with cytotoxic activity against K562 targets 6–10-fold greater than cells obtained from high- density Percoll fractions (NK-depleted cells). In coculture with marrow nonadherent cells (NA) at NK:NA ratios of 2:1, NK-enriched cells suppressed day 5–6 CFU-E to 62% (p less than 0.025) of controls, whereas NK-depleted cells slightly augmented CFU-E to 130% of controls (p greater than 0.05). In contrast, no suppression of day 10–12 marrow BFU-E was observed employing NK-enriched cells. The NK CFU-E suppressor effects were abolished by complement-mediated lysis of NK-enriched cells with the natural killer cell antibody, HNK-1. Highly purified HNK- 1+ cells separated by FACS suppressed marrow CFU-E to 34% (p less than 0.025) and marrow BFU-E to 41% (p less than 0.025) of controls. HNK- cells had no significant effect on either BFU-E or CFU-E growth. NK- enriched cells were poor stimulators of day 14 blood BFU-E in comparison to equal numbers of NK-depleted cells or T cells isolated by E-rosetting (p less than 0.01). Interferon boosting of NK-enriched cells abolished their suboptimal burst-promoting effects and augmented their CFU-E suppressor effects. These studies provide evidence for a potential regulatory role of NK cells in erythropoiesis. The NK suppressor effect is maximal at the level of the mature erythroid stem cell CFU-E. These findings may explain some hypoproliferative anemias that develop in certain NK cell-activated states.

Hemostatic Factors Contribute to Tumor Cell Metastatic Potential by a Mechanism Linked to Natural Killer Cell Function.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 690-690 ◽  
Author(s):  
Joseph S. Palumbo ◽  
Kathryn E. Talmage ◽  
Jessica V. Massari ◽  
Christine M. La Jeunesse ◽  
Matthew J. Flick ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Tumor Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Platelet Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Metastatic Potential ◽  
Natural Killer Cell Function

Abstract A linkage between hemostatic system components and tumor cell metastatic potential has been well established, but the underlying mechanism(s) by which various circulating and cell-associated coagulation factors and platelets promote tumor cell dissemination remains to be fully defined. One potential mechanism by which tumor cell-associated microthrombi might enhance metastatic potential is by interfering with the cytolytic elimination of tumor cell emboli by natural killer (NK) cells. In order to explore this hypothesis, we studied tumor dissemination in mice lacking either fibrinogen or Gαq, a G protein critical for platelet activation. Comparative studies of experimental lung metastasis in control and Gαq−/− mice showed that loss of platelet activation resulted in a two-orders-of-magnitude decrease in pulmonary metastatic foci formed by either Lewis lung carcinoma or B16 melanoma. The difference in metastatic success was not the result of differences in tumor growth rate, as tumors transplanted into the dorsal subcutis of Gαq−/− and wildtype animals grew at similar rates. Rather, tumor cell fate analyses using radiolabeled tumor cells showed that the survival of tumor cells within the lung was significantly improved in mice that retained platelet activation function relative to Gαq−/− mice with a profound platelet activation defect. In order to examine the potential interplay between platelet activation and natural killer cell function, we compared pulmonary tumor cell survival in cohorts of control and Gαq−/− mice immuno-depleted of NK cells with an anti-asialo GM1 antibody. Remarkably, platelet function was no longer a determinant of metastatic potential in mice lacking NK cells. Given that fibrin(ogen) is also an established determinant of metastatic success we explored whether the influence of this key hemostatic factor on tumor cell dissemination was also mechanistically-coupled to natural killer cell function. We interbred fibrinogen-deficient mice with Gz-Ly49A transgenic mice known to have a constitutive deficit in NK cells. In those cohorts of mice with normal NK cells, we affirmed the earlier finding that fibrinogen deficiency resulted in a significant diminution in metastatic potential. However, consistent with our findings in mice with defective platelet activation, fibrinogen was found to no longer be a determinant of metastatic potential in mice lacking NK cells. These data establish another important link between innate immune surveillance and the hemostatic system. Further, it appears that at least one mechanism by which tumor cell-associated microthrombi increase metastatic potential is by restricting NK cell-mediated tumor cell elimination. Given that NK cell cytotoxicity requires direct contact with any target cell, one attractive model presently being explored is that tumor cell-associated platelets physically block NK cell access to tumor cell emboli.

Nephrotic syndrome with crescent formation and massive IgA deposition following allogeneic bone marrow transplantation for natural killer cell leukemia/lymphoma

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 4219-4221 ◽  
Author(s):  
Shinya Kimura ◽  
Akeyo Horie ◽  
Yoshiyuki Hiki ◽  
Chie Yamamoto ◽  
Satoru Suzuki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nephrotic Syndrome ◽  
Bone Marrow Transplantation ◽  
Natural Killer Cell ◽  
Marrow Transplantation ◽  
Crescentic Glomerulonephritis ◽  
Killer Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Cell Leukemia

Abstract We describe herein a case of nephrotic syndrome (NS) following allogeneic bone marrow transplantation (allo-BMT) for natural killer cell leukemia/lymphoma. Histologic studies defined the diagnosis as crescentic glomerulonephritis with massive immunoglobulin A (IgA) deposition, which has never been reported in NS cases following allo-BMT. Most of the massive infiltrated cells in the interstice were CD3+CD4−CD8+ T cells derived from the donor. We observed mesangial deposition of Haemophilus parainfluenza outer membrane (OMHP) antigen and decreased glycosylation of the IgA1 hinge in the recipient's samples is consistent with the recently reported pathogenesis of IgA nephropathy. Further, the titer of IgA antibody against the donor serum was as high as other IgA nephropathy cases. These findings suggest that NS and crescentic glomerulonephritis in this case occurred as one of the forms of chronic graft-versus-host disease (GVHD), and that IgA deposition was associated with H parainfluenza and decreased glycosylation of the IgA1 hinge.

scholarly journals 4547 Understanding the molecular mechanism of natural killer cell deficiency to improve natural killer cell in vitro differentiation for therapeutics

2020 ◽  
Vol 4 (s1) ◽  
pp. 20-20
Author(s):  
Megan Schmit ◽  
Ryan Baxley ◽  
Emily Mace ◽  
Jordan Orange ◽  
Jeffery Miller ◽  
...  
Keyword(s):  
Dna Replication ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Premature Senescence ◽  
Replication Proteins ◽  
Telomere Erosion

OBJECTIVES/GOALS: Natural killer (NK) cells are a potential cancer therapeutic but expanding NK cells efficiently in vitro is difficult. Natural killer cell deficiency (NKD), a primary immune deficiency affecting only NK cells, is caused by defects in several DNA replication proteins. By studying NKD we will achieve better NK cell in vitro differentiation. METHODS/STUDY POPULATION: One patient with NKD has a compound heterozygous mutation in the essential DNA replication protein MCM10. We hypothesize that in individuals with NKD, dramatic telomere erosion from abnormal DNA replication leads to premature senescence and the loss of NK cells. To test our hypothesis, we will knockout one allele of MCM10 or over express MCM10 in NK cells isolated from blood. We will then monitor telomere length, expansion and cytotoxic activity of these NK cells. To understand the role of MCM10 in early stages of NK cell development we will deplete MCM10 in induced pluripotent stem cells and differentiate these cells into NK cells. During this differentiation we will monitor progression through NK cell developmental stages as well as telomere length and senescence markers. RESULTS/ANTICIPATED RESULTS: Telomeres insulate chromosomes and induce permanent growth arrest (senescence) when they are critically short. We have demonstrated that depletion of a DNA replication protein causes telomere erosion and increases senescence markers. NK cells have shorter telomeres and lower telomerase expression than other immune cells. We predict, this relatively poor telomere maintenance sensitizes NK cells to telomere loss upon depletion of replication proteins. During in vitro differentiation, we expect NK cell precursors to undergo premature senescence secondary to telomere shortening. Furthermore, we expect supplementation of DNA replication proteins will enhance NK cell expansion and maturation. DISCUSSION/SIGNIFICANCE OF IMPACT: NKD patients have provided the scientific community with clues as to what proteins NK cells rely on for their development. This project aims not only to understand why these proteins are critical, but to harness that information for cellular anti-cancer therapeutics.

scholarly journals Engraftment of Bone Marrow from Severe Combined Immunodeficient (SCID) Mice Reverses the Reproductive Deficits in Natural Killer Cell–deficient tgε26 Mice

1998 ◽  
Vol 187 (2) ◽  
pp. 217-223 ◽  
Author(s):  
Marie-Josée Guimond ◽  
Baoping Wang ◽  
B. Anne Croy
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Fetal Loss ◽  
Vascular Pathology ◽  
Metrial Gland ◽  
Unk Cell

A large, transient population of natural killer (NK) cells appears in the murine uterine mesometrial triangle during pregnancy. Depletion of uterine (u) NK cells, recently achieved using gene-ablated and transgenic mice, results in pathology. Pregnancies from matings of homozygous NK and T cell–deficient tgε26 mice have <1% of normal uNK cell frequency, no development of an implantation site–associated metrial gland, and an edematous decidua with vascular pathology that includes abnormally high vessel walls/lumens ratios. Fetal loss of 64% occurs midgestation and placentae are small. None of these features are seen in pregnant T cell–deficient mice. To confirm the role of the NK cell deficiency in these reproductive deficits, transplantation of tgε26 females was undertaken using bone marrow from B and T cell–deficient scid/scid donors. Engrafted pregnant females have restoration of the uNK cell population, induced metrial gland differentiation, reduced anomalies in the decidua and decidual blood vessels, increased placental sizes, and restoration of fetal viability at all gestational days studied (days 10, 12, and 14). Thus, uNK cells appear to have critical functions in pregnancy that promote decidual health, the appropriate vascularization of implantation sites, and placental size.

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