scholarly journals Continuous engagement of a self-specific activation receptor induces NK cell tolerance

2008 ◽  
Vol 205 (8) ◽  
pp. 1829-1841 ◽  
Author(s):  
Sandeep K. Tripathy ◽  
Peter A. Keyel ◽  
Liping Yang ◽  
Jeanette T. Pingel ◽  
Tammy P. Cheng ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Murine Cytomegalovirus ◽  
Cell Tolerance ◽  
Major Histocompatability Complex ◽  
Inhibitory Receptors ◽  
Mcmv Infection ◽  
Functional Defects

Natural killer (NK) cell tolerance mechanisms are incompletely understood. One possibility is that they possess self-specific activation receptors that result in hyporesponsiveness unless modulated by self–major histocompatability complex (MHC)–specific inhibitory receptors. As putative self-specific activation receptors have not been well characterized, we studied a transgenic C57BL/6 mouse that ubiquitously expresses m157 (m157-Tg), which is the murine cytomegalovirus (MCMV)–encoded ligand for the Ly49H NK cell activation receptor. The transgenic mice were more susceptible to MCMV infection and were unable to reject m157-Tg bone marrow, suggesting defects in Ly49H+ NK cells. There was a reversible hyporesponsiveness of Ly49H+ NK cells that extended to Ly49H-independent stimuli. Continuous Ly49H–m157 interaction was necessary for the functional defects. Interestingly, functional defects occurred when mature wild-type NK cells were adoptively transferred to m157-Tg mice, suggesting that mature NK cells may acquire hyporesponsiveness. Importantly, NK cell tolerance caused by Ly49H–m157 interaction was similar in NK cells regardless of expression of Ly49C, an inhibitory receptor specific for a self-MHC allele in C57BL/6 mice. Thus, engagement of self-specific activation receptors in vivo induces an NK cell tolerance effect that is not affected by self-MHC–specific inhibitory receptors.

scholarly journals Role for TLR2 in NK Cell-Mediated Control of Murine Cytomegalovirus In Vivo

2006 ◽  
Vol 80 (9) ◽  
pp. 4286-4291 ◽  
Author(s):  
Eva Szomolanyi-Tsuda ◽  
Xueya Liang ◽  
Raymond M. Welsh ◽  
Evelyn A. Kurt-Jones ◽  
Robert W. Finberg
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Innate Immune ◽  
Murine Cytomegalovirus ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Mcmv Infection ◽  
Toll Like Receptor 2 ◽  
Antiviral Control

ABSTRACT Natural killer (NK) cells are essential for the early control of murine cytomegalovirus (MCMV) infection. Here, we demonstrate that toll-like receptor 2 (TLR2) plays a role in the NK cell-mediated control of MCMV. TLR2 knockout (KO) mice had elevated levels of MCMV in the spleen and liver on day 4 postinfection compared to C57BL/6 mice. In vivo depletion of NK cells with anti-NK1.1 antibodies, however, eliminated the differences in viral titers between the two groups, suggesting that the effect of TLR2 on MCMV clearance on day 4 was NK cell mediated. The defect in early antiviral control was associated with a decreased NK cell population in the spleen and liver and reduced amounts of interleukin-18 and α/β interferon secreted in the TLR2 KO mice. Our studies suggest that in addition to the reported involvement of TLR9 and TLR3, TLR2 is also involved in innate immune responses to MCMV infection.

scholarly journals NK cell metabolic adaptation to infection promotes survival and viral clearance.

2021 ◽  
Author(s):  
Francisco Victorino ◽  
Tarin Bigley ◽  
Eugene Park ◽  
Cong-Hui Yao ◽  
Jeanne Benoit ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Hypoxia Inducible Factor ◽  
Murine Cytomegalovirus ◽  
Metabolic Adaptation ◽  
Mcmv Infection ◽  
Metabolic Functions ◽  
Cytokine Stimulation

Natural killer (NK) cells are essential for early protection against virus infection, and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia inducible factor-1α (HIF-1α) is a feature of NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF-1α-deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF-1α KO NK cells however, their numbers were significantly reduced. Loss of HIF-1α did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found HIF-1α-deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF-1α-deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF-1a-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.

scholarly journals Expression of Nutrient Transporters on NK Cells During Murine Cytomegalovirus Infection Is MyD88-Dependent

2021 ◽  
Vol 12 ◽  
Author(s):  
Abrar Ul Haq Khan ◽  
Saeedah Musaed Almutairi ◽  
Alaa Kassim Ali ◽  
Rosalba Salcedo ◽  
C. Andrew Stewart ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Metabolism ◽  
Interleukin 1 ◽  
High Energy ◽  
Metabolic Reprogramming ◽  
Murine Cytomegalovirus ◽  
Nutrient Transporters ◽  
Mcmv Infection

Natural killer (NK) cells are the predominant innate lymphocytes that provide early defense against infections. In the inflammatory milieu, NK cells modify their metabolism to support high energy demands required for their proliferation, activation, and functional plasticity. This metabolic reprogramming is usually accompanied by the upregulation of nutrient transporter expression on the cell surface, leading to increased nutrient uptake required for intense proliferation. The interleukin-1 family members of inflammatory cytokines are critical in activating NK cells during infection; however, their underlying mechanism in NK cell metabolism is not fully elucidated. Previously, we have shown that IL-18 upregulates the expression of solute carrier transmembrane proteins and thereby induces a robust metabolic boost in NK cells. Unexpectedly, we found that IL-18 signaling is dispensable during viral infection in vivo, while the upregulation of nutrient transporters is primarily MyD88-dependent. NK cells from Myd88-/- mice displayed significantly reduced surface expression of nutrient receptors and mTOR activity during MCMV infection. We also identified that IL-33, another cytokine employing MyD88 signaling, induces the expression of nutrient transporters but requires a pre-exposure to IL-12. Moreover, signaling through the NK cell activating receptor, Ly49H, can also promote the expression of nutrient transporters. Collectively, our findings revealed multiple pathways that can induce the expression of nutrient transporters on NK cells while highlighting the imperative role of MyD88 in NK cell metabolism during infection.

scholarly journals Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration.

1995 ◽  
Vol 182 (4) ◽  
pp. 1045-1056 ◽  
Author(s):  
J S Orange ◽  
B Wang ◽  
C Terhorst ◽  
C A Biron
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Interferon Gamma ◽  
Nk Cell ◽  
Murine Cytomegalovirus ◽  
Interleukin 12 ◽  
Mcmv Infection ◽  
Ifn Gamma ◽  
Immunodeficient Mice

The presence of natural killer (NK) cells contributes to early defense against murine cytomegalovirus (MCMV) infection. Although NK cells can mediate in vivo protection against MCMV, the mechanism by which they do so has not been defined. The studies presented here evaluate cytokine production by NK cells activated during MCMV infection and the role of NK cell-produced cytokines in early in vivo antiviral defenses. Experiments with normal C57BL/6, T cell-deficient C57BL/6 nude, and severe combined immunodeficient mice lacking T and B cells demonstrated that both interferon gamma (IFN-gamma) and tumor necrosis factor (TNF) production were induced at early times after infection with MCMV. Conditioned media samples prepared with cells from these mice, on day 2 after infection, produced 11-43 pg/million cells of IFN-gamma and 12-19 pg/million cells of TNF as evaluated by specific protein enzyme-linked immunosorbent assays. Studies in the NK- and T cell-deficient mouse line, E26, in mice that had been depleted in vivo of NK cells by treatment with antibodies eliminating NK cells, anti-asialo ganglio-N-tetraosylceramide or anti-NK1.1, and with populations of cells that had been depleted of NK cells by complement treatment with the anti-NK cell antibody, SW3A4, demonstrated that NK cells were solely responsible for the IFN-gamma but were not required for TNF production. The in vivo absence of NK cells was accompanied by increased viral hepatitis and viral replication in both immunocompetent and immunodeficient mice, as well as decreased survival time of immunodeficient mice. In vivo treatments with antibodies neutralizing IFN-gamma demonstrated that this factor contributed to the NK cell-mediated antiviral defense and reduced the measured parameters of viral defense to levels indistinguishable from those observed in NK cell-deficient mice. These effects appeared to be independent of cytolytic activity, as NK cells isolated from anti-IFN-gamma-treated mice mediated killing at levels comparable to those observed in control-treated mice. The consequences of interleukin 12 (IL-12) administration, a known potent inducer of IFN-gamma production by NK cells, were evaluated in MCMV-infected mice. Low IL-12 doses, i.e., 1 ng/d, increased NK cell cytotoxicity and IFN-gamma production up to twofold and resulted in improved antiviral status; virus-induced hepatitis was decreased as much as fivefold, and viral burdens were decreased to levels below detection.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Key features and homing properties of NK cells in the liver are shaped by activated iNKT cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Stephanie Trittel ◽  
Benedict J. Chambers ◽  
Ulrike Heise ◽  
Carlos A. Guzmán ◽  
Peggy Riese
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Viral Infections ◽  
Nk Cell ◽  
Infection Model ◽  
Inkt Cells ◽  
Mcmv Infection ◽  
Viral Loads

Abstract The contribution of natural killer (NK) cells to the clearance of hepatic viral infections is well recognized. The recently discovered heterogeneity of NK cell populations renders them interesting targets for immune interventions. Invariant natural killer T (iNKT) cells represent a key interaction partner for hepatic NK cells. The present study addressed whether characteristics of NK cells in the liver can be shaped by targeting iNKT cells. For this, the CD1d-binding pegylated glycolipid αGalCerMPEG was assessed for its ability to modulate the features of NK cells permanently or transiently residing in the liver. In vivo administration resulted in enhanced functionality of educated and highly differentiated CD27+ Mac-1+ NK cells accompanied by an increased proliferation. Improved liver homing was supported by serum-derived and cellular factors. Reduced viral loads in a mCMV infection model confirmed the beneficial effect of NK cells located in the liver upon stimulation with αGalCerMPEG. Thus, targeting iNKT cell-mediated NK cell activation in the liver represents a promising approach for the establishment of liver-directed immune interventions.

scholarly journals Viral infection modulates Qa-1b in infected and bystander cells to properly direct NK cell killing

2021 ◽  
Vol 218 (5) ◽  
Author(s):  
Maria Ferez ◽  
Cory J. Knudson ◽  
Avital Lev ◽  
Eric B. Wong ◽  
Pedro Alves-Peixoto ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Inhibitory Receptors ◽  
Inflammatory Monocytes ◽  
Activating Receptors ◽  
Infected Cells

Natural killer (NK) cell activation depends on the signaling balance of activating and inhibitory receptors. CD94 forms inhibitory receptors with NKG2A and activating receptors with NKG2E or NKG2C. We previously demonstrated that CD94-NKG2 on NK cells and its ligand Qa-1b are important for the resistance of C57BL/6 mice to lethal ectromelia virus (ECTV) infection. We now show that NKG2C or NKG2E deficiency does not increase susceptibility to lethal ECTV infection, but overexpression of Qa-1b in infected cells does. We also demonstrate that Qa-1b is down-regulated in infected and up-regulated in bystander inflammatory monocytes and B cells. Moreover, NK cells activated by ECTV infection kill Qa-1b–deficient cells in vitro and in vivo. Thus, during viral infection, recognition of Qa-1b by activating CD94/NKG2 receptors is not critical. Instead, the levels of Qa-1b expression are down-regulated in infected cells but increased in some bystander immune cells to respectively promote or inhibit their killing by activated NK cells.

scholarly journals HIF1α is required for NK cell metabolic adaptation during virus infection

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Francisco Victorino ◽  
Tarin Bigley ◽  
Eugene Park ◽  
Cong-Hui Yao ◽  
Jeanne Benoit ◽  
...  
Keyword(s):  
Virus Infection ◽  
Nk Cells ◽  
Nk Cell ◽  
Hypoxia Inducible Factor ◽  
Murine Cytomegalovirus ◽  
Metabolic Adaptation ◽  
Mcmv Infection ◽  
Cytokine Stimulation

Natural killer (NK) cells are essential for early protection against virus infection, and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia inducible factor-1α (HIF-1α) is a feature of mouse NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF-1 α -deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF-1α KO NK cells however, their numbers were significantly reduced. Loss of HIF-1 α did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found HIF-1α -deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF-1α -deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF-1α-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.

Impact of β2 integrin deficiency on mouse natural killer cell development and function

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2874-2882 ◽  
Author(s):  
Karine Crozat ◽  
Céline Eidenschenk ◽  
Baptiste N. Jaeger ◽  
Philippe Krebs ◽  
Sophie Guia ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Surface Expression ◽  
Cell Maturation ◽  
Cell Surface Expression ◽  
Mcmv Infection ◽  
Β2 Integrin

Abstract Natural killer (NK) cells are innate immune cells that express members of the leukocyte β2 integrin family in humans and mice. These CD11/CD18 heterodimers play critical roles in leukocyte trafficking, immune synapse formation, and costimulation. The cell-surface expression of one of these integrins, CD11b/CD18, is also recognized as a major marker of mouse NK-cell maturation, but its function on NK cells has been largely ignored. Using N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated a mouse carrying an A → T transverse mutation in the Itgb2 gene, resulting in a mutation that prevented the cell-surface expression of CD18 and its associated CD11a, CD11b, and CD11c proteins. We show that β2 integrin–deficient NK cells have a hyporesponsive phenotype in vitro, and present an alteration of their in vivo developmental program characterized by a selective accumulation of c-kit+ cells. NK-cell missing-self recognition was partially altered in vivo, whereas the early immune response to mouse cytomegalovirus (MCMV) infection occurred normally in CD18-deficient mice. Therefore, β2 integrins are required for optimal NK-cell maturation, but this deficiency is partial and can be bypassed during MCMV infection, highlighting the robustness of antiviral protective responses.

scholarly journals NK cell activation through the NKG2D ligand MULT-1 is selectively prevented by the glycoprotein encoded by mouse cytomegalovirus gene m145

2005 ◽  
Vol 201 (2) ◽  
pp. 211-220 ◽  
Author(s):  
Astrid Krmpotic ◽  
Milena Hasan ◽  
Andrea Loewendorf ◽  
Tanja Saulig ◽  
Anne Halenius ◽  
...  
Keyword(s):  
Cell Activation ◽  
Nk Cell ◽  
Surface Expression ◽  
Viral Gene ◽  
Nkg2d Ligand ◽  
Mouse Cytomegalovirus ◽  
Mcmv Infection ◽  
Viral Survival ◽  
Necessary And Sufficient

The NK cell–activating receptor NKG2D interacts with three different cellular ligands, all of which are regulated by mouse cytomegalovirus (MCMV). We set out to define the viral gene product regulating murine UL16-binding protein-like transcript (MULT)-1, a newly described NKG2D ligand. We show that MCMV infection strongly induces MULT-1 gene expression, but surface expression of this glycoprotein is nevertheless completely abolished by the virus. Screening a panel of MCMV deletion mutants defined the gene m145 as the viral regulator of MULT-1. The MCMV m145-encoded glycoprotein turned out to be necessary and sufficient to regulate MULT-1 by preventing plasma membrane residence of MULT-1. The importance of MULT-1 in NK cell regulation in vivo was confirmed by the attenuating effect of the m145 deletion that was lifted after NK cell depletion. Our findings underline the significance of escaping MULT-1/NKG2D signaling for viral survival and maintenance.

scholarly journals P03.24 Calreticulin exposure on malignant blasts correlates with improved NK cell-mediated cytotoxicity in AML patients

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A32.1-A32
Author(s):  
I Truxova ◽  
L Kasikova ◽  
C Salek ◽  
M Hensler ◽  
D Lysak ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Type I ◽  
Danger Signals ◽  
Hla Dr ◽  
Patient Prognosis ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

In some settings, cancer cells responding to treatment undergo an immunogenic form of cell death that is associated with the abundant emission of danger signals in the form of damage-associated molecular patterns. Accumulating preclinical and clinical evidence indicates that danger signals play a crucial role in the (re-)activation of antitumor immune responses in vivo, thus having a major impact on patient prognosis. We have previously demonstrated that the presence of calreticulin on the surface of malignant blasts is a positive prognostic biomarker for patients with acute myeloid leukemia (AML). Calreticulin exposure not only correlated with enhanced T-cell-dependent antitumor immunity in this setting but also affected the number of circulating natural killer (NK) cells upon restoration of normal hematopoiesis. Here, we report that calreticulin exposure on malignant blasts is associated with enhanced NK cell cytotoxic and secretory functions, both in AML patients and in vivo in mice. The ability of calreticulin to stimulate NK-cells relies on CD11c+CD14high cells that, upon exposure to CRT, express higher levels of IL-15Rα, maturation markers (CD86 and HLA- DR) and CCR7. CRT exposure on malignant blasts also correlates with the upregulation of genes coding for type I interferon. This suggests that CD11c+CD14high cells have increased capacity to migrate to secondary lymphoid organs, where can efficiently deliver stimulatory signals (IL-15Rα/IL- 15) to NK cells. These findings delineate a multipronged, clinically relevant mechanism whereby surface-exposed calreticulin favors NK-cell activation in AML patients.Disclosure InformationI. Truxova: None. L. Kasikova: None. C. Salek: None. M. Hensler: None. D. Lysak: None. P. Holicek: None. P. Bilkova: None. M. Holubova: None. X. Chen: None. R. Mikyskova: None. M. Reinis: None. M. Kovar: None. B. Tomalova: None. J.P. Kline: None. L. Galluzzi: None. R. Spisek: None. J. Fucikova: None.

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