scholarly journals CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice

Blood ◽  
2011 ◽  
Vol 117 (2) ◽  
pp. 451-458 ◽  
Author(s):  
Mamiko Noda ◽  
Yoshiki Omatsu ◽  
Tatsuki Sugiyama ◽  
Shinya Oishi ◽  
Nobutaka Fujii ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Development ◽  
Hematopoietic Stem ◽  
Adult Mice ◽  
Multipotent Progenitors ◽  
Chemokine Signaling ◽  
Chemokine Ligand

Abstract Natural killer (NK) cells are granular lymphocytes that are generated from hematopoietic stem cells and play vital roles in the innate immune response against tumors and viral infection. Generation of NK cells is known to require several cytokines, including interleukin-15 (IL-15) and Fms-like tyrosine kinase 3 ligand, but not IL-2 or IL-7. Here we investigated the in vivo role of CXC chemokine ligand-12 (CXCL12) and its primary receptor CXCR4 in NK-cell development. The numbers of NK cells appeared normal in embryos lacking CXCL12 or CXCR4; however, the numbers of functional NK cells were severely reduced in the bone marrow, spleen, and peripheral blood from adult CXCR4 conditionally deficient mice compared with control animals, probably resulting from cell-intrinsic CXCR4 deficiency. In culture, CXCL12 enhanced the generation of NK cells from lymphoid-primed multipotent progenitors and immature NK cells. In the bone marrow, expression of IL-15 mRNA was considerably higher in CXCL12-abundant reticular (CAR) cells than in other marrow cells, and most NK cells were in contact with the processes of CAR cells. Thus, CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adults, and CAR cells might function as a niche for NK cells in bone marrow.

scholarly journals IL-15 trans-presentation promotes human NK cell development and differentiation in vivo

2008 ◽  
Vol 206 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Nicholas D. Huntington ◽  
Nicolas Legrand ◽  
Nuno L. Alves ◽  
Barbara Jaron ◽  
Kees Weijer ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Development ◽  
Class I Mhc ◽  
Mhc I ◽  
Hematopoietic Stem ◽  
Receptor Agonists ◽  
Development And Differentiation ◽  
Therapeutic Tools

The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self–major histocompatability complex class I (MHC-I; killer Ig-like receptors [KIRs]) remain undefined. Here, we dissect the role of interleukin (IL)-15 in human NK cell development using Rag2−/−γc−/− mice transplanted with human hematopoietic stem cells. Human NK cell reconstitution was intrinsically low in this model because of the poor reactivity to mouse IL-15. Although exogenous human IL-15 (hIL-15) alone made little improvement, IL-15 coupled to IL-15 receptor α (IL-15Rα) significantly augmented human NK cells. IL-15–IL-15Rα complexes induced extensive NK cell proliferation and differentiation, resulting in accumulation of CD16+KIR+ NK cells, which was not uniquely dependent on enhanced survival or preferential responsiveness of this subset to IL-15. Human NK cell differentiation in vivo required hIL-15 and progressed in a linear fashion from CD56hiCD16−KIR− to CD56loCD16+KIR−, and finally to CD56loCD16+KIR+. These data provide the first evidence that IL-15 trans-presentation regulates human NK cell homeostasis. Use of hIL-15 receptor agonists generates a robust humanized immune system model to study human NK cells in vivo. IL-15 receptor agonists may provide therapeutic tools to improve NK cell reconstitution after bone marrow transplants, enhance graft versus leukemia effects, and increase the pool of IL-15–responsive cells during immunotherapy strategies.

scholarly journals Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice

2019 ◽  
Vol 2 (2) ◽  
pp. e201800195 ◽  
Author(s):  
Masashi Matsuda ◽  
Rintaro Ono ◽  
Tomonori Iyoda ◽  
Takaho Endo ◽  
Makoto Iwasaki ◽  
...  
Keyword(s):  
Nk Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Cell Development ◽  
Innate Immune ◽  
Humanized Mice ◽  
In Vivo Model ◽  
Hematopoietic Stem ◽  
Nsg Mice

The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies of human NK cells were confirmed in multiple organs of hIL-7 and hIL-15 double knockin (hIL-7xhIL-15 KI) NSG mice engrafted with human hematopoietic stem cells. hIL-7xhIL-15 KI NSG humanized mice provide a valuable in vivo model to investigate development and function of human NK cells.

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 TREM2 Promotes Natural Killer Cell Development in CD3-CD122+NK1.1+ pNK Cells

2020 ◽  
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/6J 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 Combining Immunocytokine and Ex Vivo Activated NK Cells as a Platform for Enhancing Graft-Versus-Tumor Effects Against GD2+ Murine Neuroblastoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Paul D. Bates ◽  
Alexander L. Rakhmilevich ◽  
Monica M. Cho ◽  
Myriam N. Bouchlaka ◽  
Seema L. Rao ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Nk Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Tnf Α

Management for high-risk neuroblastoma (NBL) has included autologous hematopoietic stem cell transplant (HSCT) and anti-GD2 immunotherapy, but survival remains around 50%. The aim of this study was to determine if allogeneic HSCT could serve as a platform for inducing a graft-versus-tumor (GVT) effect against NBL with combination immunocytokine and NK cells in a murine model. Lethally irradiated C57BL/6 (B6) x A/J recipients were transplanted with B6 bone marrow on Day +0. On day +10, allogeneic HSCT recipients were challenged with NXS2, a GD2+ NBL. On days +14-16, mice were treated with the anti-GD2 immunocytokine hu14.18-IL2. In select groups, hu14.18-IL2 was combined with infusions of B6 NK cells activated with IL-15/IL-15Rα and CD137L ex vivo. Allogeneic HSCT alone was insufficient to control NXS2 tumor growth, but the addition of hu14.18-IL2 controlled tumor growth and improved survival. Adoptive transfer of ex vivo CD137L/IL-15/IL-15Rα activated NK cells with or without hu14.18-IL2 exacerbated lethality. CD137L/IL-15/IL-15Rα activated NK cells showed enhanced cytotoxicity and produced high levels of TNF-α in vitro, but induced cytokine release syndrome (CRS) in vivo. Infusing Perforin-/- CD137L/IL-15/IL-15Rα activated NK cells had no impact on GVT, whereas TNF-α-/- CD137L/IL-15/IL-15Rα activated NK cells improved GVT by decreasing peripheral effector cell subsets while preserving tumor-infiltrating lymphocytes. Depletion of Ly49H+ NK cells also improved GVT. Using allogeneic HSCT for NBL is a viable platform for immunocytokines and ex vivo activated NK cell infusions, but must be balanced with induction of CRS. Regulation of TNFα or activating NK subsets may be needed to improve GVT effects.

scholarly journals RTID-07. HUMAN PLACENTAL HEMATOPOIETIC STEM CELL DERIVED NATURAL KILLER CELLS (CYNK-001) FOR TREATMENT OF RECURRENT GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii194-ii195
Author(s):  
Nazanin Majd ◽  
Maha Rizk ◽  
Solveig Ericson ◽  
Kris Grzegorzewski ◽  
Sharmila Koppisetti ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
In Vitro Cytotoxicity ◽  
Orthotopic Mouse Model ◽  
Hematopoietic Stem ◽  
Dismal Prognosis

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with dismal prognosis. Recent advances of immunotherapy in cancer have sparked interest in the use of cell therapy for treatment of GBM. Active transfer of Natural Killer (NK) cells is of particular interest in GBM because NK cells are capable of exerting anti-tumor cytotoxicity without the need for antigen presentation and sensitization, processes that are impaired in GBM. CYNK-001 is an allogeneic, off-the-shelf product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells manufactured by Celularity. Here, we demonstrate in vitro cytotoxicity of CYNK-001 against several GBM lines and its in vivo anti-tumor activity in a U87MG orthotopic mouse model via intracranial administration resulting in 94.5% maximum reduction in tumor volume. We have developed a phase I window-of-opportunity trial of CYNK-001 in recurrent GBM via intravenous (IV) and intratumoral (IT) routes. In the IV cohort, subjects receive cyclophosphamide for lymphodepletion followed by 3-doses of IV CYNK-001 weekly. In the IT cohort, subjects undergo placement of an IT catheter with an ommaya reservoir followed by 3-doses of IT CYNK-001 weekly. Patients are monitored for 28-days after last infusion for toxicity. Once maximum safe dose (MSD) is determined, patients undergo IV or IT treatments at MSD followed by surgical resection and the tumor tissue will be analyzed for NK cell engraftment and persistence. We will utilize a 3 + 3 dose de-escalation design (maximum n=36). Primary endpoint is safety and feasibility. Secondary endpoints are overall response rate, duration of response, time to progression, progression free survival and overall survival. Main eligibility criteria include age ≥18, KPS ≥60, GBM at first or second relapse with a measurable lesion on ≤2mg dexamethasone. This is the first clinical trial to investigate CYNK-001 in GBM and will lay the foundation for future NK cell therapy in solid tumors.

Human NK cell development in NOD/SCID mice receiving grafts of cord blood CD34+ cells

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 127-135 ◽  
Author(s):  
Christian P. Kalberer ◽  
Uwe Siegler ◽  
Aleksandra Wodnar-Filipowicz
Keyword(s):  
Cord Blood ◽  
Nk Cells ◽  
Scid Mouse ◽  
Nk Cell ◽  
Cell Development ◽  
Scid Mice ◽  
Differentiation Potential ◽  
Ifn Γ

Abstract Definition of the cytokine environment, which regulates the maturation of human natural killer (NK) cells, has been largely based on in vitro assays because of the lack of suitable animal models. Here we describe conditions leading to the development of human NK cells in NOD/SCID mice receiving grafts of hematopoietic CD34+ precursor cells from cord blood. After 1-week-long in vivo treatment with various combinations of interleukin (IL)–15, flt3 ligand, stem cell factor, IL-2, IL-12, and megakaryocyte growth and differentiation factor, CD56+CD3- cells were detected in bone marrow (BM), spleen, and peripheral blood (PB), comprising 5% to 15% of human CD45+ cells. Human NK cells of NOD/SCID mouse origin closely resembled NK cells from human PB with respect to phenotypic characteristics, interferon (IFN)–γ production, and cytotoxicity against HLA class 1–deficient K562 targets in vitro and antitumor activity against K562 erythroleukemia in vivo. In the absence of growth factor treatment, CD56+ cells were present only at background levels, but CD34+CD7+ and CD34-CD7+ lymphoid precursors with NK cell differentiation potential were detected in BM and spleen of chimeric NOD/SCID mice for up to 5 months after transplantation. Our results demonstrate that limitations in human NK cell development in the murine microenvironment can be overcome by treatment with NK cell growth–promoting human cytokines, resulting in the maturation of IFN-γ–producing cytotoxic NK cells. These studies establish conditions to explore human NK cell development and function in vivo in the NOD/SCID mouse model. (Blood. 2003;102:127-135)

STAT5 promotes multilineage hematolymphoid development in vivo through effects on early hematopoietic progenitor cells

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 95-101 ◽  
Author(s):  
Jonathan W. Snow ◽  
Ninan Abraham ◽  
Melissa C. Ma ◽  
Nancy W. Abbey ◽  
Brian Herndier ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Blood Cell ◽  
Progenitor Cells ◽  
Cell Types ◽  
Hematopoietic Stem ◽  
Signal Transducers ◽  
Adult Mice ◽  
Colony Forming Units ◽  
Proliferation Activity

The transcription factor signal transducers and activators of transcription 5 (STAT5) is activated by numerous cytokines that orchestrate blood cell development. Multilineage peripheral blood cytopenias were observed in adult mice lacking both isoforms of STAT5 (STAT5A and STAT5B) as well as accelerated rates of apoptosis in the bone marrow. Although the hematopoietic stem cell (HSC) population was preserved in a number of these mice, the post-HSC progenitor populations were diminished and a marked reduction in functional progenitors (spleen colony-forming units) was detected. Competitive bone marrow transplantation studies in vivo revealed a profound impairment of repopulation potential of STAT5-null HSCs, leading to complete lack of contribution to the myeloid, erythroid, and lymphoid lineages. These abnormalities were associated with heightened proliferation activity in the HSC fraction, suggesting the action of homeostatic mechanisms to maintain sufficient levels of diverse blood cell types for viability. Thus, STAT5 normally sustains the robust hematopoietic reserve that contributes to host viability through crucial survival effects on early progenitor cells.

The Effects of Rapamune on NK Cell Post Bone Marrow Transplantation in Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4858-4858
Author(s):  
Guanghua Chen ◽  
De Pei Wu ◽  
Ming Zhen Yang ◽  
Xiao Wen Tang ◽  
Ai-ning Sun
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Nk Cells ◽  
Marrow Transplantation ◽  
Nk Cell ◽  
Immunosuppressive Agents ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Effector Cells

Abstract Natural killer(NK) cells are innate effector cells of the immune system, believed to limit viremia and tumor burden before the onset of adaptive T and B cell immunity. NK cells are potent effector cells in allogeneic bone marrow transplantation. NK cell activity is partially controlled through interactions between killer Ig-like receptors on NK cells and their respective HLA class I ligands. Immunosuppressive agents including cyclosporin, FK506 and Rapamune are utilized in clinical hematopoietic stem cell transplantation. Little is known about the effects of immunosuppressive agents on NK cells post bone marrow transplantation. The in vivo effects of Rapamune on NK cells were determined in an allogeneic bone marrow transplantation model. Splenic NK cell levels in recipients treated with Rapamune decrease markedly. NK cell proliferation and function are significantly decreased in the presence of Rapamune. Studying the differential effects of immunosuppressive drugs on NK cell function is critical in clinical hematopoietic stem cell transplantation.

In Vivo Development of Murine NK Cells Early after Congeneic BMT: Effects of MHC Molecules, and the Administration of hIL-15.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2334-2334
Author(s):  
Isabel Barao-Silvestre ◽  
Doug Redelman ◽  
Erik Ames ◽  
Jonathan Weiss ◽  
Kai Sun ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Allelic Variation ◽  
Surface Expression ◽  
Lymphoid Cells ◽  
Temporary Increase ◽  
Mature Adult ◽  
Mhc Molecules ◽  
Adult Mice

Abstract Natural Killer (NK) cells are lymphocytes of the innate immune system that are able to kill a variety of tumors and pathogen-infected cells without prior sensitization. NK cells are the first lymphoid cells to repopulate following bone marrow transplantation (BMT). The present study shows that murine NK cells developing in vivo after BMT are phenotypically and functionally distinguishable from mature adult NK cells. Using a congeneic BMT mouse model (CD45.1/H-2b → C57BL/6, CD45.2/H-2b) we demonstrated here that donor derived BM-NK progenitors (CD122+NK1.1-CD3-)were present in the BM and periphery (spleen), at day 14 after BMT, and developed into NK cells expressing high levels of CD122, NKG2D, CD94, DX5 and CD43. However, surface expression of Ly49 inhibitory receptors was altered with Ly49C/I being under-expressed (9.8 %± 3.2 %), and Ly49G2 being highly expressed (62 %± 3.1 %) when compared to NK cells from non-transplanted adult mice (Ly49C/I, 43.1 %± 7.6 % and Ly49G2, 44.3 %± 13.5 %). At 28 days after BMT, there was a normalization with regard to Ly49 phenotype. The developing NK cells manifested functional deficits compared to non-transplanted adult NK, even when stimulated in vitro with Interleukin (IL)-2, as evidenced by decreased interferongamma (IFN-g) production and cytolytic activity. In order to examine the effects of major histocompatibility complex (MHC) molecules on NK development independently of allelic variation of Ly49s, we performed syngeneic BMT using B10D2 mice (H-2d). We observed the same pattern of Ly49s expression during NK development demonstrating that the acquisition of these receptors early after BMT is not determined by the MHC haplotype. Because IL-15 plays a crucial role in NK cell development, we administrated human (h) IL-15, via hydrodynamic injection of the respective gene, at day 11 after BMT, to accelerate NK maturation. This method resulted in a high but transient production of hIL-15 (736 ± 41 pg/ml) in the serum for up to 2 weeks. A subsequent but temporary increase in the numbers of donor derived NK cells (3 fold) occurred within 72 hours, in both BM and periphery, following hIL-15 gene delivery. Despite these augmenting effects, the developing NK cells still exhibited poor functionality compared to non-transplanted adult mice. These studies describe the possibility of NK development in the spleen, and indicate that normal surface expression of Ly49C/I and Ly49G2 early after BMT is time dependent, but MHC independent. Moreover, administration of hIL-15 is not sufficient to induce NK functional maturation early after BMT despite increased NK numbers.

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