scholarly journals Interleukin-12 is chemotactic for natural killer cells and stimulates their interaction with vascular endothelium

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2261-2268
Author(s):  
P Allavena ◽  
C Paganin ◽  
D Zhou ◽  
G Bianchi ◽  
S Sozzani ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Vascular Endothelium ◽  
Nk Cell ◽  
Interleukin 12 ◽  
Polymorphonuclear Cells ◽  
Activated T Cells ◽  
Cell Recruitment

We investigated the chemotactic activity of interleukin (IL)-12 on human natural killer (NK) cells and other leukocyte subsets. It was found that IL-12 induced directional migration of highly enriched preparations of NK cells (> 80% CD16+ and CD56+) and CD3-activated T cells (both of CD4 and CD8 subset), but not resting T cells and monocytes. On the contrary, purified polymorphonuclear cells (PMN) showed significant and reproducible chemotactic response to IL-12. The effects of IL-12 on leukocyte migration were observed in a narrow concentration range with a peak at approximately 7.5 ng/mL, and were abrogated by monoclonal antibody (MoAb) anti-IL-12 or after cytokine boiling. We also investigated the interaction of NK cells with vascular endothelium in vitro. Overnight treatment of NK cells with IL-12 augmented their binding to cultured endothelial cells (EC) obtained from umbilical veins. IL-12-increased binding was better observed when resting rather than IL-1-activated EC were used as substratum of adhesion. IL-12-augmented binding of NK cells to resting or IL-1- activated EC involved the LFA-1/ICAM-1 and VLA-4/VCAM-1 pathways. Thus, by inducing migration and interaction with EC, IL-12 regulates crucial determinants of NK-cell recruitment in tissues.

scholarly journals Interleukin-12 is chemotactic for natural killer cells and stimulates their interaction with vascular endothelium

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2261-2268 ◽  
Author(s):  
P Allavena ◽  
C Paganin ◽  
D Zhou ◽  
G Bianchi ◽  
S Sozzani ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Vascular Endothelium ◽  
Nk Cell ◽  
Interleukin 12 ◽  
Polymorphonuclear Cells ◽  
Activated T Cells ◽  
Cell Recruitment

Abstract We investigated the chemotactic activity of interleukin (IL)-12 on human natural killer (NK) cells and other leukocyte subsets. It was found that IL-12 induced directional migration of highly enriched preparations of NK cells (> 80% CD16+ and CD56+) and CD3-activated T cells (both of CD4 and CD8 subset), but not resting T cells and monocytes. On the contrary, purified polymorphonuclear cells (PMN) showed significant and reproducible chemotactic response to IL-12. The effects of IL-12 on leukocyte migration were observed in a narrow concentration range with a peak at approximately 7.5 ng/mL, and were abrogated by monoclonal antibody (MoAb) anti-IL-12 or after cytokine boiling. We also investigated the interaction of NK cells with vascular endothelium in vitro. Overnight treatment of NK cells with IL-12 augmented their binding to cultured endothelial cells (EC) obtained from umbilical veins. IL-12-increased binding was better observed when resting rather than IL-1-activated EC were used as substratum of adhesion. IL-12-augmented binding of NK cells to resting or IL-1- activated EC involved the LFA-1/ICAM-1 and VLA-4/VCAM-1 pathways. Thus, by inducing migration and interaction with EC, IL-12 regulates crucial determinants of NK-cell recruitment in tissues.

Fibronectin maintains survival of mouse natural killer (NK) cells via CD11b/Src/β-catenin pathway

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4081-4088 ◽  
Author(s):  
Ting Zhang ◽  
Shuxun Liu ◽  
Pengyuan Yang ◽  
Chaofeng Han ◽  
Jianli Wang ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nuclear Translocation ◽  
Nk Cell ◽  
Ex Vivo ◽  
Interleukin 12 ◽  
Erk Phosphorylation ◽  
Extracellular Signal ◽  
B Cell Leukemia

Abstract Tissue microenvironment and stroma-derived extracellular matrix (ECM) molecules play important roles in the survival and differentiation of cells. Mouse natural killer (NK) cells usually die within 24 hours once isolated ex vivo. Exogenous cytokines such as interleukin-12 (IL-12) and IL-15 are required to maintain the survival and activity of mouse NK cells cultured in vitro. Whether and how ECM molecules such as fibronectin can support the survival of NK cells remain unknown. We demonstrate that fibronectin, just like IL-15, can maintain survival of mouse NK cells in vitro. Furthermore, we show that fibronectin binds to the CD11b on NK cells, and then CD11b recruits and activates Src. Src can directly interact with β-catenin and trigger nuclear translocation of β-catenin. The activation of β-catenin promotes extracellular signal-related kinase (ERK) phosphorylation, resulting in the increased expression of antiapoptotic protein B-cell leukemia 2 (Bcl-2), which may contribute to the maintenance of NK-cell survival. Consistently, fibronectin cannot maintain the survival of CD11b− NK cells and β-catenin–deficient NK cells in vitro, and the number of NK cells is dramatically decreased in the β-catenin–deficient mice. Therefore, fibronectin can maintain survival of mouse NK cells by activating ERK and up-regulating Bcl-2 expression via CD11b/Src/β-catenin pathway.

scholarly journals Molecules and structures involved in the adhesion of natural killer cells to vascular endothelium.

1991 ◽  
Vol 173 (2) ◽  
pp. 439-448 ◽  
Author(s):  
P Allavena ◽  
C Paganin ◽  
I Martin-Padura ◽  
G Peri ◽  
M Gaboli ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Adhesion Molecule ◽  
Vascular Endothelium ◽  
Nk Cell ◽  
Leukocyte Adhesion ◽  
Umbilical Vein ◽  
Interleukin 2 ◽  
Intercellular Adhesion Molecule

The present study was designed to define molecules and structures involved in the interaction of natural killer (NK) cells with the vascular endothelium in vitro. Resting and interleukin 2 (IL-2)-activated NK cells were studied for their capacity to adhere to resting and IL-1-treated human umbilical vein endothelial cells (EC). In the absence of stimuli, NK cells showed appreciable adhesion to EC, with levels of binding intermediate between polymorphs and monocytes. The binding ability was increased by pretreatment of NK cells with IL-2. Using the appropriate monoclonal antibody, the beta 2 leukocyte integrin CD18/CD11a was identified as the major adhesion pathway of NK cells to unstimulated EC. Activation of EC with IL-1 increased the binding of NK cells. In addition to the CD18-CD11a/intercellular adhesion molecule pathway, the interaction of resting or IL-2-activated NK cells to IL-1-activated EC involved the VLA-4 (alpha 4 beta 1)-vascular cell adhesion molecule 1 receptor/counter-receptor pair. No evidence for appreciable involvement of endothelial-leukocyte adhesion molecule was obtained. Often, NK cells interacted either with the culture substrate or with the EC surface via dot-shaped adhesion structures (podosomes) protruding from the ventral surface and consisting of a core of F-actin surrounded by a ring of vinculin and talin. The identification of molecules and microanatomical structures involved in the interaction of NK cells with EC may provide a better understanding of the regulation of NK cell recruitment from blood, their extravasation, and their migration to tissues.

Elevated CD54 Expression Renders CD4+ T Cells Susceptible to Natural Killer Cell-Mediated Killing

2019 ◽  
Vol 220 (12) ◽  
pp. 1892-1903 ◽  
Author(s):  
Xi Chen ◽  
Huihui Chen ◽  
Zining Zhang ◽  
Yajing Fu ◽  
Xiaoxu Han ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cd4 T Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Adaptive Immune Response ◽  
Phenotypic Analysis

Abstract Background Natural killer (NK) cells are an important type of effector cell in the innate immune response, and also have a role in regulation of the adaptive immune response. Several studies have indicated that NK cells may influence CD4+ T cells during HIV infection. Methods In total, 51 HIV-infected individuals and 15 healthy controls participated in this study. We performed the flow cytometry assays and real-time PCR for the phenotypic analysis and the functional assays of NK cell-mediated deletion of CD4+ T cells, phosphorylation of nuclear factor-κB (NF-κB/p65) and the intervention of metformin. Results Here we detected high CD54 expression on CD4+ T cells in HIV-infected individuals, and demonstrate that upregulated CD54 is associated with disease progression in individuals infected with HIV. We also show that CD54 expression leads to the deletion of CD4+ T cells by NK cells in vitro, and that this is modulated by NF-κB/p65 signaling. Further, we demonstrate that metformin can suppress CD54 expression on CD4+ T cells by inhibiting NF-κB/p65 phosphorylation. Conclusions Our data suggest that further studies to evaluate the potential role of metformin as adjunctive therapy to reconstitute immune function in HIV-infected individuals are warranted.

Contribution of Natural Killer Cells to Inhibition of Angiogenesis by Interleukin-12

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1612-1621 ◽  
Author(s):  
Lei Yao ◽  
Cecilia Sgadari ◽  
Keizo Furuke ◽  
Eda T. Bloom ◽  
Julie Teruya-Feldstein ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Primary Cultures ◽  
Interleukin 12 ◽  
Ifn Γ

Abstract Interleukin-12 (IL-12) inhibits angiogenesis in vivo by inducing interferon-γ (IFN-γ) and other downstream mediators. Here, we report that neutralization of natural killer (NK) cell function with antibodies to either asialo GM1 or NK 1.1 reversed IL-12 inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis in athymic mice. By immunohistochemistry, those sites where bFGF-induced neovascularization was inhibited by IL-12 displayed accumulation of NK cells and the presence of IP-10–positive cells. Based on expression of the cytolytic mediators perforin and granzyme B, the NK cells were locally activated. Experimental Burkitt lymphomas treated locally with IL-12 displayed tumor tissue necrosis, vascular damage, and NK-cell infiltration surrounding small vessels. After activation in vitro with IL-12, NK cells from nude mice became strongly cytotoxic for primary cultures of syngeneic aortic endothelial cells. Cytotoxicity was neutralized by antibodies to IFN-γ. These results document that NK cells are required mediators of angiogenesis inhibition by IL-12, and provide evidence that NK-cell cytotoxicity of endothelial cells is a potential mechanism by which IL-12 can suppress neovascularization.

Natural-killer cells and dendritic cells: “l'union fait la force”

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2252-2258 ◽  
Author(s):  
Thierry Walzer ◽  
Marc Dalod ◽  
Scott H. Robbins ◽  
Laurence Zitvogel ◽  
Eric Vivier
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Interleukin 12 ◽  
Cell Contact ◽  
Ifn Γ

AbstractSeveral recent publications have focused on the newly described interactions between natural-killer (NK) cells and dendritic cells (DCs). Activated NK cells induce DC maturation either directly or in synergy with suboptimal levels of microbial signals. Immature DCs appear susceptible to autologous NK-cell-mediated cytolysis while mature DCs are protected. NK-cell-induced DC activation is dependent on both tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ) secretion and a cell-cell contact involving NKp30. In vitro, interleukin-12 (IL-12)/IL-18, IL-15, and IFN-α/β production by activated DCs enhance, in turn, NK-cell IFN-γ production, proliferation, and cytotoxic potential, respectively. In vivo, NK-cell/DC interactions may occur in lymphoid organs as well as in nonlymphoid tissues, and their consequences are multiple. By inducing DC activation, NK-cell activation induced by tumor cells can indirectly promote antitumoral T-cell responses. Reciprocally, DCs activated through Toll-like receptors (TLRs) induce potent NK-cell activation in antiviral responses. Thus, DCs and NK cells are equipped with complementary sets of receptors that allow the recognition of various pathogenic agents, emphasizing the role of NK-cell/DC crosstalk in the coordination of innate and adaptive immune responses.

scholarly journals Receptor-induced death in human natural killer cells: involvement of CD16.

1995 ◽  
Vol 181 (1) ◽  
pp. 339-344 ◽  
Author(s):  
J R Ortaldo ◽  
A T Mason ◽  
J J O'Shea
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Nk Cells ◽  
Natural Killer ◽  
Tyrosine Kinases ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Activated T Cells ◽  
Human Natural Killer Cells ◽  
Induced Apoptosis

Propriocidal regulation of T cells refers to apoptosis induced by interleukin 2 (IL-2) activation with subsequent antigen receptor stimulation. We examined whether natural killer (NK) cells exhibited cytokine- and ligand-induced death similar to activated T cells. Peripheral NK cells were examined for ligand-induced death using antibodies to surface moieties (CD2, CD3, CD8, CD16, CD56), with and without prior activation of IL-2. Only those NK cells stimulated first with IL-2 and then with CD16 exhibited ligand-induced death; none of the other antibody stimuli induced this phenomenon. Next we examined various cytokines (IL-2, IL-4, IL-6, IL-7, IL-12, IL-13, interferon alpha and gamma) that can activate NK cells and determined if CD16-induced killing occurred. Only IL-2 and IL-12 induced NK cell death after occupancy of this receptor by aggregated immunoglobulin or by cross-linking with antireceptor antibody. The CD16-induced death was inhibited by herbimycin A, indicating that cell death was dependent upon protein tyrosine kinases. Identical to T cells, the form of cell death for NK cells was demonstrated to be receptor-induced apoptosis. Overall these data indicate that highly activated NK cells mediate ligand-induced apoptosis via signaling molecules like CD16. Whereas the propriocidal regulation of T cells is antigen specific, this is not the case for NK cells due to the nature of the receptor. The clinical implications of this finding are considered.

Contribution of Natural Killer Cells to Inhibition of Angiogenesis by Interleukin-12

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1612-1621 ◽  
Author(s):  
Lei Yao ◽  
Cecilia Sgadari ◽  
Keizo Furuke ◽  
Eda T. Bloom ◽  
Julie Teruya-Feldstein ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Primary Cultures ◽  
Interleukin 12 ◽  
Ifn Γ

Interleukin-12 (IL-12) inhibits angiogenesis in vivo by inducing interferon-γ (IFN-γ) and other downstream mediators. Here, we report that neutralization of natural killer (NK) cell function with antibodies to either asialo GM1 or NK 1.1 reversed IL-12 inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis in athymic mice. By immunohistochemistry, those sites where bFGF-induced neovascularization was inhibited by IL-12 displayed accumulation of NK cells and the presence of IP-10–positive cells. Based on expression of the cytolytic mediators perforin and granzyme B, the NK cells were locally activated. Experimental Burkitt lymphomas treated locally with IL-12 displayed tumor tissue necrosis, vascular damage, and NK-cell infiltration surrounding small vessels. After activation in vitro with IL-12, NK cells from nude mice became strongly cytotoxic for primary cultures of syngeneic aortic endothelial cells. Cytotoxicity was neutralized by antibodies to IFN-γ. These results document that NK cells are required mediators of angiogenesis inhibition by IL-12, and provide evidence that NK-cell cytotoxicity of endothelial cells is a potential mechanism by which IL-12 can suppress neovascularization.

scholarly journals Definition of a natural killer NKR-P1A+/CD56-/CD16- functionally immature human NK cell subset that differentiates in vitro in the presence of interleukin 12.

1996 ◽  
Vol 184 (5) ◽  
pp. 1845-1856 ◽  
Author(s):  
I M Bennett ◽  
O Zatsepina ◽  
L Zamai ◽  
L Azzoni ◽  
T Mikheeva ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Subset ◽  
Interleukin 12 ◽  
Ifn Gamma ◽  
Differentiation Antigens ◽  
Nk Cell Differentiation

Human natural killer (NK) cell differentiation from immature lineage negative (Lin-) umbilical cord blood cells was examined in vitro. Cells expressing differentiation antigens of mature NK cells (CD56, CD16, CD2, CD8, NKR-P1A) were generated from Lin- cells cultured with interleukin (IL)-2 and a murine bone marrow stromal cell line expressing the human membrane-bound form of stem cell factor. Two subsets of NK cells were identified in these cultures: one expressed both NKR-P1A and CD56 and, in variable proportions, all other NK cell differentiation antigens; the second subset expressed only NKR-P1A and, unlike the former, was not cytotoxic. Neither subset expressed interferon (IFN)-gamma mRNA even after stimulation with phorbol di-ester and Ca2+ ionophore, but both expressed tumor necrosis factor alpha mRNA and the cytotoxic granule-associated proteins TIA-1, perforin, and serine esterase-1. After 10-d culture with IL-2, IL-12, and irradiated B lymphoblastoid cells, approximately 45% of the NKR-P1A+/ CD56- cells became CD56+, and the same cultures contained cells capable of cytotoxicity and of IFN-gamma production. These results indicate that NKR-P1A expression in the absence of other NK cell markers defines an intermediate, functionally immature stage of NK cell differentiation, and that effector functions develop in these cells, concomitantly with CD56 expression, in the presence of IL-12. These cells likely represent the counterpart of a CD3-/NKR-P1A+/ CD56-/CD16- cell subset that, as shown here, is present both in adult and neonatal circulating lymphocytes.

Natural Killer Cells Derived From Human Pluripotent Stem Cells Provide a Novel Method to Treat HIV-1 Infection.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 280-280
Author(s):  
Zhenya Ni ◽  
David A. Knorr ◽  
Christine L. Clouser ◽  
Peter Southern ◽  
Louis M. Mansky ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Progenitor Cells ◽  
Pluripotent Stem Cells ◽  
Nk Cell ◽  
Infected Cells ◽  
Hiv 1

Abstract Abstract 280 Natural killer (NK) cells are known to be key components of the innate immune system with the ability to kill diverse tumor cells and virally infected cells. Our group has previously demonstrated derivation of CD45+CD56+ natural killer (NK) cells from human embryonic stem cells (hESCs)-derived hematopoietic CD34+CD45+ progenitor cells. These hESC-derived NK cells demonstrate potent killing of various tumor cells both in vitro and in vivo. More recently, we have also successfully generated NK cells from similar CD34+CD45+ hematopoietic progenitor cells derived from human induced pluripotent stem cells (iPSCs). Again, we find that these iPSC-derived NK cells also have effective anti-tumor activity in vitro. Notably, both the hESC and iPSC-derived NK cells are uniformly CD94+CD117−, corresponding to a more mature and cytotoxic NK cell population. This is in contrast to NK cells derived from umbilical cord blood (UCB) progenitor cells that produce a mixture of CD94+CD117− and CD94−CD117+ NK cells that are more heterogeneous in their cytotoxic activity. Previous studies of NK cells isolated from peripheral blood indicate they have activity against HIV-1-infected cells. Therefore, we hypothesized that both hESC and iPSC-derived NK cells would be able to kill HIV-1-infected targets. We have applied multiple complementary systems to test this hypothesis using both HIV-1-infected cell lines and HIV-1-infected primary T cells. First, we used a chronically infected cell line (H9/HTLV IIIB) to demonstrate specific cytolytic activity of hESC-derived NK cells. Here, we found CD107a expression (a marker of NK cell functional activity) was significantly upregulated on hESC-derived effectors stimulated by the HIV-1-infected targets compared to uninfected targets (13.7% vs. 4.3%). Next, we utilized primary human CD4 T cells infected with primary patient isolate HIV96-480 as targets to demonstrate the same effect to specifically activate both hESC and iPSC-derived NK cells. In both of these studies, control NK cell populations derived from human umbilical cord blood progenitor cells were significantly less active against HIV than the hESC and iPSC-derived NK cells. In addition to the cytolytic function against HIV-1-infected targets, we demonstrate hESC and iPSC-derived NK cells also suppress HIV-1 replication by producing CC-chemokines to competitively inhibit CCR5 co-receptor binding. CCL4 (MIP1b), a CCR5 ligand, is greatly induced in both hESC and iPSC-derived NK cells after incubation with HIV-1-infected targets compared to uninfected targets: 37.2% (HIV-infected) vs. 24.8% (uninfected) for hESC-NK cells and 32.5% (HIV-infected) vs. 21.6% (uninfected) for iPSC-NK cells. Lastly, we have also tested suppression of acute HIV-1 infection by hESC-derived NK cells in vitro. Here, the T-cell line CEM-GFP was infected with HIV-1 NL4-3 and cocultured with hESC-derived NK cells for two weeks. HIV-1-infected targets detected by flow cytometry for GFP expression were strongly decreased in comparison to controls in absence of NK cells (% of GFP+ cells: 0.74 vs. 26.4). In these analyses, expression of CD107a and CCL4 on the effectors again correlates with the inhibition of HIV-1 replication. Currently, as hESC and iPSC-derived NK cells express the Fc receptor CD16, we are using anti-envelope protein antibodies against HIV-1 infected primary human CD4 T cells to determine if antibody-dependent cellular cytotoxicity provides another mechanism of lytic activity for these novel NK cells. Collectively, our results demonstrate that NK cells derived from hESCs and iPSCs provide an effective novel cellular immunotherapy for HIV-1 infection. Disclosures: No relevant conflicts of interest to declare.

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