scholarly journals Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection

2014 ◽  
Vol 211 (13) ◽  
pp. 2669-2680 ◽  
Author(s):  
Gundula Min-Oo ◽  
Lewis L. Lanier
Keyword(s):  
Nk Cells ◽  
Host Response ◽  
Ex Vivo ◽  
Specific Response ◽  
Type I ◽  
Secondary Challenge ◽  
Acute Viral Infection ◽  
Ifn Γ ◽  
Systemic Bacterial Infection ◽  
Memory Nk Cells

Natural killer (NK) cells play a key role in the host response to cytomegalovirus (CMV) and can mediate an enhanced response to secondary challenge with CMV. We assessed the ability of mouse CMV (MCMV)–induced memory Ly49H+ NK cells to respond to challenges with influenza, an acute viral infection localized to the lung, and Listeria monocytogenes, a systemic bacterial infection. MCMV-memory NK cells did not display enhanced activation or proliferation after infection with influenza or Listeria, as compared with naive Ly49H+ or Ly49H− NK cells. Memory NK cells also showed impaired activation compared with naive cells when challenged with a mutant MCMV lacking m157, highlighting their antigen-specific response. Ex vivo, MCMV-memory NK cells displayed reduced phosphorylation of STAT4 and STAT1 in response to stimulation by IL-12 and type I interferon (IFN), respectively, and IFN-γ production was reduced in response to IL-12 + IL-18 compared with naive NK cells. However, costimulation of MCMV-memory NK cells with IL-12 and m157 antigen rescues their impaired response compared with cytokines alone. These findings reveal that MCMV-primed memory NK cells are diminished in their response to cytokine-driven bystander responses to heterologous infections as they become specialized and antigen-specific for the control of MCMV upon rechallenge.

scholarly journals Strain-Specific Human Natural Killer Cell Recognition of Influenza A Virus

2017 ◽  
Author(s):  
Lisa M. Kronstad ◽  
Christof Seiler ◽  
Rosemary Vergara ◽  
Susan P. Holmes ◽  
Catherine A. Blish
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Influenza A ◽  
Nk Cell ◽  
Killer Cell ◽  
Specific Response ◽  
Cell Detection ◽  
Type I ◽  
Human Natural Killer Cell ◽  
Ifn Γ

AbstractInnate Natural killer (NK) cells employ an array of surface receptors to detect ‘altered self’ induced by infection or malignancy. Despite their decisive role in early antiviral immunity, the cellular mechanisms governing if or how they discriminate between viral infections remain unresolved. Here, we demonstrate that while human NK cells are capable of reducing infection levels of distinct influenza A strains, the A/California/07/2009 (pH1N1) strain induces a significantly more robust IFN-γ response than A/Victoria/361/2011 (H3N2) and all other strains tested. This surprising degree of strain specificity results in part from the inability of the pH1N1 strain to downregulate the activating ligands CD112 (Nectin-2) and CD54 (ICAM-1) as efficiently as the H3N2 strain, leading to enhanced NK cell detection and IFN-γ secretion. A network analysis of differentially expressed transcripts identifies the interferon α/β receptor (IFNAR) pathway as an additional, critical determinant of this strain-specific response. Strain-specific downregulation of NK cell activating ligands and modulation of type I IFN production represents a previously unrecognized influenza immunoevasion tactic and could present new opportunities to modulate the quality and quantity of the innate antiviral response for therapeutic benefit.One Sentence SummaryHuman natural killer cells distinguish between Influenza A strains using a combinatorial cytokine priming and receptor-ligand signaling mechanism.

scholarly journals HIV-1-induced cytokines deplete homeostatic ILCs and expand TCF7-dependent memory NK cells: Supplemental Figures and Tables

2017 ◽  
Author(s):  
Yetao Wang ◽  
Kyle Gellatly ◽  
Sean McCauley ◽  
Pranitha Vangala ◽  
Kyusik Kim ◽  
...  
Keyword(s):  
Nk Cells ◽  
Inflammatory Cytokines ◽  
Nk Cell ◽  
Ex Vivo ◽  
Developmental Trajectory ◽  
Lymphoid Cells ◽  
Infected People ◽  
Cell Induction ◽  
Hiv 1 ◽  
Memory Nk Cells

HIV-1-infected people who take medications that suppress viremia, preserve CD4+ T cells, and prevent AIDS, have chronic inflammation with increased cardiovascular mortality. To investigate the etiology of this inflammation, the effect of HIV-1 on innate lymphoid cells (ILCs) and NK cells was examined. Homeostatic ILCs in blood and intestine were depleted permanently. NK cells were skewed towards a memory subset. Cytokines that are elevated during HIV-1 infection reproduced both abnormalities ex vivo. Pseudotime analysis of single NK cell transcriptomes revealed a developmental trajectory towards a subset with expression profile, chromatin state, and biological function like memory T lymphocytes. Expression of TCF7, a WNT transcription factor, increased over the course of the trajectory. TCF7 disruption, or WNT inhibition, prevented memory NK cell induction by inflammatory cytokines. These results demonstrate that inflammatory cytokines associated with HIV-1 infection irreversibly disrupt homeostatic ILCs and cause developmental shift towards TCF7+ memory NK cells.

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

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2417 ◽  
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.

Ex Vivo Expansion of Highly Purified Human NK Cells..

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2157-2157
Author(s):  
Chunji Gao ◽  
Xiaohong Li ◽  
Jian Ma ◽  
Xiaoxiong Wu ◽  
Feifei Wang ◽  
...  
Keyword(s):  
Nk Cells ◽  
High Purity ◽  
Cell Expansion ◽  
Ex Vivo ◽  
Granzyme B ◽  
Ex Vivo Expansion ◽  
Biological Functions ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Ifn Γ

Abstract Abstract 2157 Poster Board II-134 Object To optimize the expansion of high purity NK cells from human peripheral blood and explore the changes in biological functions of NK cells after Ex vivo expansion. Methods NK cells were isolated from PBMNC by using miniMACS (Magnetic cell-selection) and NK Cell Isolation Kit II(Miltenyi Biotec, Germany), then they were cultured in SCEM (Stemline Hematopoietic Stem Cell Expansion Medium, Sigma) supplemented with 10% human AB serum and different combinations of interleukin (IL)-2 and/or IL-12, IL-15 for 15 days. Cultures were fed with fresh media and cytokines every 3 days, and were evaluated for cell expansion, phenotype, perforin and granzyme B mRNA expressions, and IFN-γ secretion at the end of the culture period. Results In group IL2+IL15 and IL2+IL15+IL12, cells were expanded 50.46±4.31 and 52.35±6.72 fold, respectively, much more higher than others(P<0.01), but no significant difference between them (P>0.05). And the purity of CD3−CD56+NK cells was over 94% in all groups except the control. The expressions of perforin and granzyme B mRNA of expanded NK cells cultured with cytokines was significantly higher than the starting population(P<0.01), although IL2+IL15+IL12 group was slightly higher than that of IL2+IL15 group, without significant difference (P>0.05). There was great increase in IFN-γ levels in the supernatants of NK cells culture in the presence of cytokines; IL2+IL15+IL12 group and IL2+IL12 group was significantly higher than others(P<0.01). Conclusion High purity NK cells could be efficiently expanded in culture with IL2+IL15, and its biological functions were enhanced in this condition. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Binding of Excreted and/or Secreted Products of Adult Hookworms to Human NK Cells in Necator americanus-Infected Individuals from Brazil

2008 ◽  
Vol 76 (12) ◽  
pp. 5810-5816 ◽  
Author(s):  
Andréa Teixeira-Carvalho ◽  
Ricardo T. Fujiwara ◽  
Erik J. Stemmy ◽  
Denise Olive ◽  
Jesse M. Damsker ◽  
...  
Keyword(s):  
Nk Cells ◽  
Transforming Growth Factor ◽  
Nk Cell ◽  
Ex Vivo ◽  
Interleukin 10 ◽  
Receptor Expression ◽  
Necator Americanus ◽  
Ifn Γ ◽  
The Impact

ABSTRACT The impact of the interaction between excreted and/or secreted (ES) Necator americanus products and NK cells from Necator-infected individuals was analyzed. We investigated the binding of ES products to NK cells, the expression of NK cell receptors (CD56, CD159a/NKG2A, CD314/NKG2D, CD335/NKp46, and KLRF1/NKp80), the frequency of gamma interferon (IFN-γ)-producing NK cells after whole-blood in vitro stimulation, and the capacity of N. americanus ES products to induce NK cell chemotaxis. In contrast to those from noninfected individuals, NK cells from Necator-infected individuals demonstrated no binding with N. americanus ES products. This phenomenon was not due to alterations in NK cell receptor expression in infected subjects and could not be reproduced with NK cells from uninfected individuals by incubation with immunoregulatory cytokines (interleukin-10/transforming growth factor β). Further, we found that a significantly greater percentage of NK cells from infected subjects than NK cells from uninfected individuals spontaneously produced IFN-γ upon ex vivo culture. Our findings support a model whereby NK cells from Necator-infected individuals may interact with ES products, making these cells refractory to binding with exogenous ES products. During N. americanus infection, human NK cells are attracted to the site of infection by chemotactic ES products produced by adult Necator worms in the gut mucosa. Binding of ES products causes the NK cells to become activated and secrete IFN-γ locally, thereby contributing to the adult hookworm's ability to evade host immune responses.

Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL)

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3617-3623 ◽  
Author(s):  
Shino Hanabuchi ◽  
Norihiko Watanabe ◽  
Yi-Hong Wang ◽  
Yui-Hsi Wang ◽  
Tomoki Ito ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Tumor Necrosis Factor Receptor ◽  
Type I ◽  
Cell Cytotoxicity ◽  
Cpg Odn ◽  
Ifn Γ ◽  
Nk Cell Cytotoxicity ◽  
Necrosis Factor

Plasmacytoid dendritic cell precursors (pDCs) are professional type I interferon-producing cells, a critical cell type in regulating innate and adaptive immune responses. By microarray gene expression analysis, we found that pDCs activated by virus or CpG-ODN preferentially express the ligand for the glucocorticoid-induced tumor necrosis factor receptor (GITRL), which was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry analysis. Using the same approaches, we found GITR is expressed by activated natural killer (NK) cells and T cells. We show that pDCs activated by CpG-ODN promote NK cell cytotoxicity and interferon (IFN)-γ production through type I IFNs and GITRL. Using a GITRL-transfected cell line, we further demonstrate that GITRL promotes NK cell cytotoxicity and IFN-γ production in synergy with interleukin-2 (IL-2), IFN-α, and NKG2D triggering. We also demonstrated that pDCs localized in close contact to NK cells in T-cell areas of the tonsils, and a subpopulation of the pDCs expressed GITRL. This study reveals a novel function of GITR/GITRL in pDC-mediated coactivation of NK cells.

scholarly journals Lycopene Prolongs the Lifespan and Enhances the Cytotoxicity of NK Cells after Ex Vivo Expansion

2015 ◽  
Vol 1 (1) ◽  
pp. 8
Author(s):  
Qi Li ◽  
Ting Huyan ◽  
Lin-Jie Ye ◽  
Jun-Ling Shi ◽  
Qing-Sheng Huang
Keyword(s):  
Nk Cells ◽  
Fruits And Vegetables ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Biological Effects ◽  
Ex Vivo Expansion ◽  
Peripheral Blood Mononuclear ◽  
Study Results ◽  
Ifn Γ ◽  
Positive Effect

Lycopene is a nonprovitamin A carotenoid mainly found in fruits and vegetables, which has been reported to possess a variety of biological effects. The properties of lycopene on human natural killer (NK) cells after ex vivo expansion were assessed in the present study. Results showed that lycopene has a positive effect on NK cells viability and cytotoxicity. Aging and apoptosis started from the fourth week onwards in the cultured NK cells which were obtained from the peripheral blood mononuclear cells (PBMC). Supplemented with lycopene (5μM) can restore the decreased viability and cytotoxicity of NK cells and reduce NK cells apoptosis caused by aging during fourth-sixth week culture. Its anti-apoptosis effect in NK cells may be related to lycopene which can decrease the expression of caspase 3 and 9 genes. Furthermore, lycopene can enhance the IFN-γ expression in gene and protein level after 7d treatment. However, lycopene did not affect the functional receptor’s (NKG2A, NKG2D, NKp30 and NKp44) expression on NK cells. These results indicated that lycopene has a positive effect on NK cells. As a health product, it may help to prolong the lifespan and enhance the cytotoxicity of NK cells after ex vivo expansion.

scholarly journals Proinflammatory cytokine signaling required for the generation of natural killer cell memory

2012 ◽  
Vol 209 (5) ◽  
pp. 947-954 ◽  
Author(s):  
Joseph C. Sun ◽  
Sharline Madera ◽  
Natalie A. Bezman ◽  
Joshua N. Beilke ◽  
Mark H. Kaplan ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Interleukin 12 ◽  
Cytokine Signaling ◽  
Mcmv Infection ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Memory Nk Cells

Although natural killer (NK) cells are classified as innate immune cells, recent studies demonstrate that NK cells can become long-lived memory cells and contribute to secondary immune responses. The precise signals that promote generation of long-lived memory NK cells are unknown. Using cytokine receptor-deficient mice, we show that interleukin-12 (IL-12) is indispensible for mouse cytomegalovirus (MCMV)-specific NK cell expansion and generation of memory NK cells. In contrast to wild-type NK cells that proliferated robustly and resided in lymphoid and nonlymphoid tissues for months after MCMV infection, IL-12 receptor–deficient NK cells failed to expand and were unable to mediate protection after MCMV challenge. We further demonstrate that a STAT4-dependent IFN-γ–independent mechanism contributes toward the generation of memory NK cells during MCMV infection. Understanding the full contribution of inflammatory cytokine signaling to the NK cell response against viral infection will be of interest for the development of vaccines and therapeutics.

scholarly journals NK cells require IL-28R for optimal in vivo activity

2015 ◽  
Vol 112 (18) ◽  
pp. E2376-E2384 ◽  
Author(s):  
Fernando Souza-Fonseca-Guimaraes ◽  
Arabella Young ◽  
Deepak Mittal ◽  
Ludovic Martinet ◽  
Claudia Bruedigam ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Metastasis ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Type I ◽  
Type Iii ◽  
Ifn Γ ◽  
Type Iii Ifn ◽  
Deficient Mice

Natural killer (NK) cells are naturally circulating innate lymphoid cells that protect against tumor initiation and metastasis and contribute to immunopathology during inflammation. The signals that prime NK cells are not completely understood, and, although the importance of IFN type I is well recognized, the role of type III IFN is comparatively very poorly studied. IL-28R–deficient mice were resistant to LPS and cecal ligation puncture-induced septic shock, and hallmark cytokines in these disease models were dysregulated in the absence of IL-28R. IL-28R–deficient mice were more sensitive to experimental tumor metastasis and carcinogen-induced tumor formation than WT mice, and additional blockade of interferon alpha/beta receptor 1 (IFNAR1), but not IFN-γ, further enhanced metastasis and tumor development. IL-28R–deficient mice were also more susceptible to growth of the NK cell-sensitive lymphoma, RMAs. Specific loss of IL-28R in NK cells transferred into lymphocyte-deficient mice resulted in reduced LPS-induced IFN-γ levels and enhanced tumor metastasis. Therefore, by using IL-28R–deficient mice, which are unable to signal type III IFN-λ, we demonstrate for the first time, to our knowledge, the ability of IFN-λ to directly regulate NK cell effector functions in vivo, alone and in the context of IFN-αβ.

scholarly journals Phenotypic and functional characteristics of a novel influenza hemagglutinin-specific memory NK cell

2021 ◽  
Author(s):  
Jian Zheng ◽  
Liyan Wen ◽  
Hui-Ling Yen ◽  
Ming Liu ◽  
Yinping Liu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Subset ◽  
Influenza Virus Infection ◽  
Immune Memory ◽  
Influenza Hemagglutinin ◽  
Ifn Γ ◽  
Memory Nk Cells

Immune memory represents the most efficient defense against invasion and transmission of infectious pathogens. In contrast to memory T and B cells, the roles of innate immunity in recall responses remain inconclusive. In this study, we identified a novel mouse spleen NK cell subset expressing NKp46 and NKG2A induced by intranasal influenza virus infection. These memory NK cells specifically recognize N-linked glycosylation sites on influenza hemagglutinin (HA) protein. Different from memory-like NK cells reported previously, these NKp46+NKG2A+ memory NK cells exhibited HA-specific silence of cytotoxicity but increase of IFN-γ response against influenza virus-infected cells, which could be reversed by Pifithrin-μ, a p53-HSP70 signaling inhibitor. During recall responses, splenic NKp46+NKG2A+ NK cells were recruited to infected lung and modulated viral clearance of virus and CD8+ T cell distribution, resulting in improved clinical outcomes. This long-lived NK memory bridges innate and adaptive immune memory response and promotes the homeostasis of local environment during recall response. Importance In this study, we demonstrate a novel HA-specific NKp46+NKG2A+ NK cell subset induced by influenza A virus infection. These memory NK cells show virus-specific decreased cytotoxicity and increased IFN-γ on re-encountering the same influenza virus antigen. In addition, they modulate host recall responses and CD8 T cell distribution, thus bridging the innate immune and adaptive immune responses during influenza virus infection.

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