scholarly journals Identification of the earliest natural killer cell–committed progenitor in murine bone marrow

Blood ◽  
2011 ◽  
Vol 118 (20) ◽  
pp. 5439-5447 ◽  
Author(s):  
John W. Fathman ◽  
Deepta Bhattacharya ◽  
Matthew A. Inlay ◽  
Jun Seita ◽  
Holger Karsunky ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Fate ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Lineage Commitment ◽  
Color Flow ◽  
Cell Commitment

Abstract Natural killer (NK) cells develop in the bone marrow and are known to gradually acquire the ability to eliminate infected and malignant cells, yet the cellular stages of NK lineage commitment and maturation are incompletely understood. Using 12-color flow cytometry, we identified a novel NK-committed progenitor (pre-NKP) that is a developmental intermediate between the upstream common lymphoid progenitor and the downstream NKP, previously assumed to represent the first stage of NK lineage commitment. Our analysis also refined the purity of NKPs (rNKP) by 6-fold such that 50% of both pre-NKP and rNKP cells gave rise to NKp46+ NK cells at the single-cell level. On transplantation into unconditioned Rag2−/−Il2rγc−/− recipients, both pre-NKPs and rNKPs generated mature NK cells expressing a repertoire of Ly49 family members that degranulated on stimulation ex vivo. Intrathymic injection of these progenitors, however, yielded no NK cells, suggesting a separate origin of thymic NK cells. Unlike the rNKP, the pre-NKP does not express IL-2Rβ (CD122), yet it is lineage committed toward the NK cell fate, adding support to the theory that IL-15 signaling is not required for NK commitment. Taken together, our data provide a high-resolution in vivo analysis of the earliest steps of NK cell commitment and maturation.

scholarly journals Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 926 ◽  
Author(s):  
Stefania Mantovani ◽  
Barbara Oliviero ◽  
Stefania Varchetta ◽  
Dalila Mele ◽  
Mario U. Mondelli
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Escape ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Current Status ◽  
Tumor Immune Escape

Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

scholarly journals Activated Natural Killer Cells Withstand the Relatively Low Glucose Concentrations Found in the Bone Marrow of Multiple Myeloma Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Femke A. I. Ehlers ◽  
Niken M. Mahaweni ◽  
Timo I. Olieslagers ◽  
Gerard M. J. Bos ◽  
Lotte Wieten
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Ex Vivo ◽  
Cell Cytotoxicity ◽  
Glucose Levels ◽  
Low Glucose ◽  
Nk Cell Cytotoxicity

Infusion of ex vivo expanded and cytokine-activated natural killer (NK) cells is a promising alternative way to treat multiple myeloma (MM). However, the tumor microenvironment (TME) may suppress their function. While reduced glucose availability is a TME hallmark of many solid tumors, glucose levels within the TME of hematological malignancies residing in the bone marrow (BM) remain unknown. Here, we measured glucose levels in the BM of MM patients and tested the effect of different glucose levels on NK cells. BM glucose levels were measured using a biochemical analyzer. Compared to the normal range of blood glucose, BM glucose levels were lower in 6 of 9 patients (479-1231 mg/L; mean=731.8 mg/L). The effect of different glucose levels on NK cell cytotoxicity was tested in 4-hour cytotoxicity assays with tumor cells. 500 mg/L glucose (representing low range of MM BM) during the 4-hour cytotoxicity assay did not negatively affect cytotoxicity of activated NK cells, while higher glucose concentrations (4000 mg/L) diminished NK cell cytotoxicity. Since clinical application of NK cell therapy might require ex vivo expansion, expanded NK cells were exposed to a range of glucose concentrations from 500-4000 mg/L for a longer period (4 days). This did not reduce cytotoxicity or IFN-γ secretion nor affected their phenotypic profile. In summary, low glucose concentrations, as found in BM of MM patients, by itself did not compromise the anti-tumor potential of IL-2 activated NK cells in vitro. Although follow up studies in models with a more complex TME would be relevant, our data suggest that highly activated NK cells could be used to target tumors with a reduced glucose environment.

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.

scholarly journals T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow

2014 ◽  
Vol 211 (3) ◽  
pp. 563-577 ◽  
Author(s):  
Cécile Daussy ◽  
Fabrice Faure ◽  
Katia Mayol ◽  
Sébastien Viel ◽  
Georg Gasteiger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Fetal Liver ◽  
Killer Cell ◽  
Ectopic Expression ◽  
Nkt Cells ◽  
Lymphoid Cells ◽  
Cell Lineages

Trail+DX5−Eomes− natural killer (NK) cells arise in the mouse fetal liver and persist in the adult liver. Their relationships with Trail−DX5+ NK cells remain controversial. We generated a novel Eomes-GFP reporter murine model to address this question. We found that Eomes− NK cells are not precursors of classical Eomes+ NK cells but rather constitute a distinct lineage of innate lymphoid cells. Eomes− NK cells are strictly dependent on both T-bet and IL-15, similarly to NKT cells. We observed that, in the liver, expression of T-bet in progenitors represses Eomes expression and the development of Eomes+ NK cells. Reciprocally, the bone marrow (BM) microenvironment restricts T-bet expression in developing NK cells. Ectopic expression of T-bet forces the development of Eomes− NK cells, demonstrating that repression of T-bet is essential for the development of Eomes+ NK cells. Gene profile analyses show that Eomes− NK cells share part of their transcriptional program with NKT cells, including genes involved in liver homing and NK cell receptors. Moreover, Eomes− NK cells produce a broad range of cytokines, including IL-2 and TNF in vitro and in vivo, during immune responses against vaccinia virus. Thus, mutually exclusive expression of T-bet and Eomes drives the development of different NK cell lineages with complementary functions.

scholarly journals Tumor growth impedes natural-killer-cell maturation in the bone marrow

Blood ◽  
2006 ◽  
Vol 108 (1) ◽  
pp. 246-252 ◽  
Author(s):  
John O. Richards ◽  
Xing Chang ◽  
Bradley W. Blaser ◽  
Michael A. Caligiuri ◽  
Pan Zheng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Growth ◽  
Nk Cells ◽  
Natural Killer ◽  
Bone Marrow Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Functional Maturation ◽  
Ifn Γ

Natural-killer (NK)-cell dysfunction and IFN-γ deficiencies have been associated with increased incidence of both malignancy and infection. The immunologic basis of NK-cell defects in cancer-bearing hosts has not been extensively studied. Here, we demonstrate that multiple lineages of tumors, including thymoma, breast cancer, colon cancer, and melanoma cell lines, interrupt functional maturation during NK-cell development in the bone marrow. The immature NK cells in the periphery of tumor-bearing mice had impaired IFN-γ production but seemingly normal cytotoxicity. T cells are not involved in this NK maturation arrest, because T-cell depletion did not restore NK-cell development. Moreover, the extent of tumor-cell infiltration into the bone marrow does not correlate with defective NK maturation. Interestingly, the defect was associated with a significant reduction in the IL-15Rα+ cells in the non-T, non-NK compartment of bone marrow cells and restored by overexpression of IL-15. Our data demonstrate that tumor growth can impede functional maturation of NK cells, most likely by interrupting the requisite IL-15 signaling pathway. (Blood. 2006;108:246-252)

scholarly journals Adoptive Natural Killer Cell Immunotherapy for Canine Osteosarcoma

2021 ◽  
Vol 8 ◽  
Author(s):  
William C. Kisseberth ◽  
Dean A. Lee
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Ex Vivo ◽  
Metastatic Cancer ◽  
Killer Cell ◽  
Therapeutic Interventions ◽  
Primary Bone Tumor ◽  
Cell Immunotherapy

Osteosarcoma is the most common primary bone tumor in both humans and dogs. It is a highly metastatic cancer and therapy has not improved significantly since the inclusion of adjuvant chemotherapy into disease treatment strategies. Osteosarcoma is an immunogenic tumor, and thus development of immunotherapies for its treatment, especially treatment of microscopic pulmonary metastases might improve outcomes. NK cells are lymphocytes of the innate immune system and can recognize a variety of stressed cells, including cancer cells, in the absence of major histocompatibility complex (MHC)-restricted receptor ligand interactions. NK cells have a role in controlling tumor progression and metastasis and are important mediators of different therapeutic interventions. The core hypothesis of adoptive natural killer (NK) cell therapy is there exists a natural defect in innate immunity (a combination of cancer-induced reduction in NK cell numbers and immunosuppressive mechanisms resulting in suppressed function) that can be restored by adoptive transfer of NK cells. Here, we review the rationale for adoptive NK cell immunotherapy, NK cell biology, TGFβ and the immunosuppressive microenvironment in osteosarcoma, manufacturing of ex vivo expanded NK cells for the dog and provide perspective on the present and future clinical applications of adoptive NK cell immunotherapy in spontaneous osteosarcoma and other cancers in the dog.

scholarly journals TREM2 promotes natural killer cell development in CD3−CD122+NK1.1+ pNK cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hwa-Youn Lee ◽  
Eun-Hee Lee ◽  
Jawoon Yi ◽  
Kon-Young Ji ◽  
Su-Man Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Inflammatory Responses ◽  
Bone Marrow Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Antitumor Effects ◽  
Hematopoietic Stem

Abstract Background Triggering receptor expressed on myeloid cells 2 (TREM2) signaling is considered to regulate anti-inflammatory responses in macrophages, dendritic cell maturation, osteoclast development, induction of obesity, and Alzheimer’s disease pathogenesis. However, little is known regarding the effect of TREM2 on natural killer (NK) cells. Results Here, we demonstrated for the first time that CD3−CD122+NK1.1+ precursor NK (pNK) cells expressed TREM2 and their population increased in TREM2-overexpressing transgenic (TREM2-TG) mice compared with that in female C57BL/6 J wild type (WT) mice. Both NK cell-activating receptors and NK cell-associated genes were expressed at higher levels in various tissues of TREM2-TG mice than in WT mice. In addition, bone marrow-derived hematopoietic stem cells (HSCs) of TREM2-TG mice (TG-HSCs) successfully differentiated into NK cells in vitro, with a higher yield from TG-HSCs than from WT-HSCs. In contrast, TREM2 signaling inhibition by TREM2-Ig or a phosphatidylinositol 3-kinase (PI3K) inhibitor affected the expression of the NK cell receptor repertoire and decreased the expression levels of NK cell-associated genes, resulting in significant impairment of NK cell differentiation. Moreover, in melanoma-bearing WT mice, injection of bone marrow cells from TREM2-TG mice exerted greater antitumor effects than that with cells from WT control mice. Conclusions Collectively, our data clearly showed that TREM2 promoted NK cell development and tumor regression, suggesting TREM2 as a new candidate for cancer immunotherapy.

scholarly journals Natural killer cell activation related to clinical outcome of COVID-19

2020 ◽  
Author(s):  
Christopher Maucourant ◽  
Iva Filipovic ◽  
Andrea Ponzetta ◽  
Soo Aleman ◽  
Martin Cornillet ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Viral Infections ◽  
Nk Cell ◽  
Severe Disease ◽  
Killer Cell ◽  
Interaction Network ◽  
Host Responses ◽  
Color Flow

Understanding innate immune responses in COVID-19 is important for deciphering mechanisms of host responses and interpreting disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes that respond to acute viral infections, but might also contribute to immune pathology. Here, using 28-color flow cytometry, we describe a state of strong NK cell activation across distinct subsets in peripheral blood of COVID-19 patients, a pattern mirrored in scRNA-seq signatures of lung NK cells. Unsupervised high-dimensional analysis identified distinct immunophenotypes that were linked to disease severity. Hallmarks of these immunophenotypes were high expression of perforin, NKG2C, and Ksp37, reflecting a high presence of adaptive NK cell expansions in circulation of patients with severe disease. Finally, arming of CD56bright NK cells was observed in course of COVID-19 disease states, driven by a defined protein-protein interaction network of inflammatory soluble factors. This provides a detailed map of the NK cell activation-landscape in COVID-19 disease.

Synergistic effects of in vivo depletion of Ly-49A and Ly-49G2 natural killer cell subsets in the rejection of H2b bone marrow cell allografts

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3840-3844 ◽  
Author(s):  
Arati Raziuddin ◽  
Michael Bennett ◽  
Robin Winkler-Pickett ◽  
John R. Ortaldo ◽  
Dan L. Longo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Bone Marrow Cell ◽  
Nk Cell ◽  
Synergistic Effects ◽  
Marrow Cell ◽  
Killer Cell ◽  
F1 Hybrids

Subsets of murine natural killer (NK) cells exist that express the Ly-49 family of molecules that recognize different major histocompatibility complex (MHC) determinants. Bone marrow transplantation studies were performed to examine the in vivo functions of 2 of these subsets. Subsets of Ly-49A and Ly-49G2 NK share specificity for the same MHC class 1 ligand, Dd, binding of which results in an inhibitory signal to the NK cell but allows them to lyse H2b targets in vitro. We therefore examined the ability of these subsets to reject H2b bone marrow cell allografts in lethally irradiated mice. Surprisingly, depletion of Ly-49A+ NK cells in BALB/c or B10.D2 mice (both H2d) had no effect on the rejection of H2b BMC. However, Ly-49A depletion did partially abrogate the ability of B10.BR (H2k) mice to reject H2ballografts. Although depletion of either Ly-49A+ or Ly-49G2+ NK cells alone had no effect on the ability of B10.D2 mice to reject H2b BMC, depletion of both subsets dramatically and synergistically abrogated rejection. Studies with various B10 congenic mice and their F1 hybrids indicate that this synergy between Ly49A and Ly4G2 depletion occurs in every instance. Thus, Ly-49A+ NK cells appear to play a role in the rejection H2b bone marrow allografts, but, in most strains of mice studied, Ly-49G2+ NK cells must also be eliminated. The putative roles of these NK cell subsets in clinical transplantation remains to be elucidated.

scholarly journals Natural killer cell immunotypes related to COVID-19 disease severity

2020 ◽  
Vol 5 (50) ◽  
pp. eabd6832 ◽  
Author(s):  
Christopher Maucourant ◽  
Iva Filipovic ◽  
Andrea Ponzetta ◽  
Soo Aleman ◽  
Martin Cornillet ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Disease Severity ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Nk Cell ◽  
Severe Disease ◽  
Killer Cell ◽  
Interaction Network ◽  
Color Flow

Understanding innate immune responses in COVID-19 is important to decipher mechanisms of host responses and interpret disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes that respond to acute viral infections but might also contribute to immunopathology. Using 28-color flow cytometry, we here reveal strong NK cell activation across distinct subsets in peripheral blood of COVID-19 patients. This pattern was mirrored in scRNA-seq signatures of NK cells in bronchoalveolar lavage from COVID-19 patients. Unsupervised high-dimensional analysis of peripheral blood NK cells furthermore identified distinct NK cell immunotypes that were linked to disease severity. Hallmarks of these immunotypes were high expression of perforin, NKG2C, and Ksp37, reflecting increased presence of adaptive NK cells in circulation of patients with severe disease. Finally, arming of CD56bright NK cells was observed across COVID-19 disease states, driven by a defined protein-protein interaction network of inflammatory soluble factors. This study provides a detailed map of the NK cell activation landscape in COVID-19 disease.

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