The Canarypox-virus vaccine vector ALVAC triggers the release of IFN-γ by Natural Killer (NK) cells enhancing Th1 polarization

Abstract Dendritic cells (DCs) play a crucial role in naive T-cell priming. Recent data suggested that natural killer (NK) cells can influence the capability of DCs to promote Th1 polarization. This regulatory function is primarily mediated by cytokines released in the microenvironment during inflammatory responses involving NK cells. In this study, we show that human NK cells exposed for short time to interleukin (IL)–12, IL-2, or IL-18, promote distinct pathways of Th1 priming. IL-12– or IL-2–conditioned NK cells induce maturation of DCs capable of priming IFN-γ–producing Th1 cells. On the other hand, IL-18–conditioned NK cells induce Th1 polarization only when cocultured with both DCs and T cells. In this case, IL-2 released by T cells and IL-12 derived from DCs during the priming process promote interferon (IFN)–γ production. In contrast, when NK cells are exposed to IL-4, nonpolarized T cells releasing only low levels of IL-2 are generated. Thus, the prevalence of IL-12, IL-2, IL-18, or IL-4 at inflammatory sites may differentially modulate the NK-cell interaction with DCs, leading to different outcomes in naive T-cell polarization.

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Tumour cell vaccines that secrete interleukin-2 (IL-2) and interferonγ (IFN-γ) are recognised by T cells while resisting destruction by natural killer (NK) cells

European Journal of Cancer ◽

10.1016/0959-8049(96)00099-8 ◽

1996 ◽

Vol 32 (8) ◽

pp. 1408-1412 ◽

Cited By ~ 7

Author(s):

K.S. Zier ◽

B. Gansbacher

Keyword(s):

T Cells ◽

Nk Cells ◽

Natural Killer ◽

Tumour Cell ◽

Interleukin 2 ◽

Ifn Γ

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Aberrant anti-viral response of natural killer cells in severe asthma

European Respiratory Journal ◽

10.1183/13993003.02422-2018 ◽

2020 ◽

Vol 55 (5) ◽

pp. 1802422

Author(s):

Justine Devulder ◽

Cécile Chenivesse ◽

Valérie Ledroit ◽

Stéphanie Fry ◽

Pierre-Emmanuel Lobert ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Severe Asthma ◽

Cell Activation ◽

Mononuclear Cells ◽

Nk Cell ◽

Peripheral Blood Mononuclear ◽

Healthy Donors ◽

Asthma Patients ◽

Ifn Γ

Rhinovirus infections are the main cause of asthma exacerbations. As natural killer (NK) cells are important actors of the antiviral innate response, we aimed at evaluating the functions of NK cells from severe asthma patients in response to rhinovirus-like molecules or rhinoviruses.Peripheral blood mononuclear cells from patients with severe asthma and healthy donors were stimulated with pathogen-like molecules or with the rhinoviruses (RV)-A9 and RV-2. NK cell activation, degranulation and interferon (IFN)-γ expression were analysed.NK cells from severe asthma patients were less cytotoxic than those from healthy donors in response to toll-like receptor (TLR)3, TLR7/8 or RV-A9 but not in response to RV-2 stimulation. Furthermore, when cultured with interleukin (IL)-12+IL-15, cytokines which are produced during viral infections, NK cells from patients with severe asthma were less cytotoxic and expressed less IFN-γ than NK cells from healthy donors. NK cells from severe asthmatics exhibited an exhausted phenotype, with an increased expression of the checkpoint molecule Tim-3.Together, our findings indicate that the activation of NK cells from patients with severe asthma may be insufficient during some but not all respiratory infections. The exhausted phenotype may participate in NK cell impairment and aggravation of viral-induced asthma exacerbation in these patients.

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Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells

Blood ◽

10.1182/blood-2012-03-415364 ◽

2012 ◽

Vol 119 (24) ◽

pp. 5758-5768 ◽

Cited By ~ 86

Author(s):

Saar Gill ◽

Adrianne E. Vasey ◽

Alysha De Souza ◽

Jeanette Baker ◽

Aaron T. Smith ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Rapid Development ◽

Receptor Expression ◽

Down Regulation ◽

First Response ◽

Control Tumor Growth ◽

Control Tumor ◽

Ifn Γ

Abstract Natural killer (NK) cells are potent anti-viral and antitumor “first responders” endowed with natural cytotoxicity and cytokine production capabilities. To date, attempts to translate these promising biologic functions through the adoptive transfer of NK cells for the treatment of cancer have been of limited benefit. Here we trace the fate of adoptively transferred murine NK cells and make the surprising observation that NK cells traffic to tumor sites yet fail to control tumor growth or improve survival. This dysfunction is related to a rapid down-regulation of activating receptor expression and loss of important effector functions. Loss of interferon (IFN)γ production occurs early after transfer, whereas loss of cytotoxicity progresses with homeostatic proliferation and tumor exposure. The dysfunctional phenotype is accompanied by down-regulation of the transcription factors Eomesodermin and T-bet, and can be partially reversed by the forced overexpression of Eomesodermin. These results provide the first demonstration of NK-cell exhaustion and suggest that the NK-cell first-response capability is intrinsically limited. Further, novel approaches may be required to circumvent the described dysfunctional phenotype.

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Breaking the co-operation between bystander T-cells and natural killer cells prevents the development of immunosuppression after traumatic skeletal muscle injury in mice

Clinical Science ◽

10.1042/cs20140835 ◽

2015 ◽

Vol 128 (11) ◽

pp. 825-838 ◽

Cited By ~ 6

Author(s):

Florian Wirsdörfer ◽

Jörg M. Bangen ◽

Eva Pastille ◽

Wiebke Hansen ◽

Stefanie B. Flohé

Keyword(s):

Skeletal Muscle ◽

T Cells ◽

Nk Cells ◽

Natural Killer ◽

Muscle Injury ◽

Adaptive Immune System ◽

Th Cells ◽

Skeletal Muscle Injury ◽

Ifn Γ

Nosocomial infections represent serious complications after traumatic or surgical injuries in intensive care units. The pathogenesis of the underlying immunosuppression is only incompletely understood. In the present study, we investigated whether injury interferes with the function of the adaptive immune system in particular with the differentiation of antigen-specific T helper (Th)-cell responses in vivo. We used a mouse model for traumatic gastrocnemius muscle injury. Ovalbumin (OVA), which served as a foreign model antigen, was injected into the hind footpads for determination of the differentiation of OVA-specific Th-cells in the draining popliteal lymph node (pLN). The release of interferon (IFN)-γ from OVA-specific Th-cells was impaired within 24 h after injury and this impairment persisted for at least 7 days. In contrast, the proliferation of OVA-specific Th-cells remained unaffected. Injury did not modulate the function of antigen-presenting cells (APCs) in the pLN. Adoptive transfer of total T-cells from pLNs of injured mice inhibited IFN-γ production by OVA-specific Th-cells in naive mice. Suppressed Th1 priming did not occur in lymphocyte-deficient mice after injury but was restored by administration of T-cells before injury. Moreover, the suppression of Th1 differentiation required the presence of natural killer (NK) cells that were recruited to the pLN after injury; this recruitment was dependent on lymphocytes, toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). In summary, upon traumatic skeletal muscle injury T-cells and NK cells together prevent the development of protective Th1 immunity. Breaking this co-operation might be a novel approach to reduce the risk of infectious complications after injury.

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TIM-3 Expression Is Downregulated on Human NK Cells in Response to Cancer Targets in Synergy with Activation

Cancers ◽

10.3390/cancers12092417 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2417 ◽

Cited By ~ 1

Author(s):

Tram N. Dao ◽

Sagar Utturkar ◽

Nadia Atallah Lanman ◽

Sandro Matosevic

Keyword(s):

T Cell ◽

Nk Cells ◽

Natural Killer ◽

Interferon Gamma ◽

Nk Cell ◽

Ex Vivo ◽

Cell Dysfunction ◽

Nk Cell Receptors ◽

Ifn Γ

Among natural killer (NK) cell receptors, the T-cell immunoglobulin and mucin-containing domain (TIM-3) has been associated with both inhibitory and activating functions, depending on context and activation pathway. Ex vivo and in vitro, expression of TIM-3 is inducible and depends on activation stimulus. Here, we report that TIM-3 expression can be downregulated on NK cells under specific conditions. When NK cells are exposed to cancer targets, they synergize with stimulation conditions to induce a substantial decrease in TIM-3 expression on their surface. We found that such downregulation occurs following prior NK activation. Downregulated TIM-3 expression correlated to lower cytotoxicity and lower interferon gamma (IFN-γ) expression, fueling the notion that TIM-3 might function as a benchmark for human NK cell dysfunction.

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

Blood ◽

10.1182/blood.v93.5.1612 ◽

1999 ◽

Vol 93 (5) ◽

pp. 1612-1621 ◽

Cited By ~ 127

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.

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Effect of interleukins (IL-2, IL-15, IL-18) on receptors activation and cytotoxic activity of natural killer cells in breast cancer cell

African Health Sciences ◽

10.4314/ahs.v20i2.36 ◽

2020 ◽

Vol 20 (2) ◽

pp. 822-832 ◽

Cited By ~ 2

Author(s):

Wahyu Widowati ◽

Diana K Jasaputra ◽

Sutiman B Sumitro ◽

Mochammad A Widodo ◽

Tjandrawati Mozef ◽

...

Keyword(s):

Breast Cancer ◽

Cytotoxic Activity ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Cell Receptor ◽

Mcf7 Cells ◽

Activating Receptors ◽

Tnf Α ◽

Ifn Γ

Introduction: Breast cancer is one of the leading cause of cancer deaths in women. Metastasis in BC is caused by immuno- surveillance deficiency, such NK cell maturation, low NK activity and decreasing cytotoxicity. This study was performed to improve activating receptors and cytotoxicity of NK cells using interleukins (ILs). Methods: Human recombinant IL-2, -15, and -18 were used to induce NK cells. We measured the activating and inhibiting receptors, proliferation activity of NK cells, and the cytotoxicity of NK cells on BC cells (MCF7). The effects of ILs were tested on the NK cell receptors CD314, CD158a and CD107a with flowcytometry, proliferation at various incubation times with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and concen- trations of TNF-α and IFN-γ by NK cells with ELISA. Results: ILs increased NK cell receptor levels (CD314, CD158a, and CD107a) at 24 hours of incubation. ILs increased NK cell viability, which increased with longer incubation. Moreover, ILs-induced NK cells inhibited proliferation in MCF7 cells, as well as increased TNF-α, IFN-γ, PRF1 and GzmB secretion. Conclusion: IL-2, IL-15, and IL-18 improved activating receptors and proliferation of NK cells. IL-induced NK cells in- creased TNF-α, IFN-γ, PRF1 and GzmB secretion and cytotoxic activity on BC cells. High NK cell numbers increased BC cell growth inhibition. Keywords: Activator; breast cancer; interleukins; natural killer; receptor.

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Histaminergic regulation of interferon‐gamma (IFN‐γ) production by human natural killer (NK) cells

Clinical & Experimental Immunology ◽

10.1046/j.1365-2249.1996.d01-755.x ◽

1996 ◽

Vol 105 (2) ◽

pp. 376-382 ◽

Cited By ~ 18

Author(s):

A. ASEA ◽

M. HANSSON ◽

C. CZERKINSKY ◽

T. HOUZE ◽

S. HERMODSSON ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Interferon Gamma ◽

Ifn Γ

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A novel role for reciprocal CD30-CD30L signaling in the cross-talk between natural killer and dendritic cells

Biological Chemistry ◽

10.1515/bc-2011-213 ◽

2012 ◽

Vol 393 (1-2) ◽

pp. 101-106 ◽

Cited By ~ 12

Author(s):

Vijaya Lakshmi Simhadri ◽

Hinrich P. Hansen ◽

Venkateswara R. Simhadri ◽

Katrin S. Reiners ◽

Martina Bessler ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Nk Cells ◽

Natural Killer ◽

Cross Talk ◽

Mitogen Activated Protein Kinase ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Ifn Γ ◽

The Cross

Abstract The interplay between dendritic cells (DCs) and natural killer (NK) cells directs adaptive immune responses. The molecular basis of the cross-talk is largely undefined. Here, we provide evidence for a contribution of CD30 (TNFRSF8) and its ligand CD30L (TNFSF8) expressed on NK cells and DCs, respectively. We demonstrate that CD30-mediated engagement of CD30L induced cytokine secretion from immature DCs via the mitogen-activated protein kinase pathway. Moreover, CD30L engagement promoted differentiation to mature DCs. On the contrary, the engagement of CD30 on NK cells resulted in an NF-κB-dependent release of TNF-α/IFN-γ. These data uncover a novel and unexpected role for CD30/CD30L that contributes to proinflammatory immune responses.

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