scholarly journals Multiplicity and plasticity of natural killer cell signaling pathways

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2364-2372 ◽  
Author(s):  
Sabrina Chiesa ◽  
Michael Mingueneau ◽  
Nicolas Fuseri ◽  
Bernard Malissen ◽  
David H. Raulet ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Interferon Γ ◽  
Effector Functions ◽  
Activating Receptors ◽  
Cell Effector

AbstractNatural killer (NK) cells express an array of activating receptors that associate with DAP12 (KARAP), CD3ζ, and/or FcRγ ITAM (immunoreceptor tyrosine-based activation motif)–bearing signaling subunits. In T and mast cells, ITAM-dependent signals are integrated by critical scaffolding elements such as LAT (linker for activation of T cells) and NTAL (non–T-cell activation linker). Using mice that are deficient for ITAM-bearing molecules, LAT or NTAL, we show that NK cell cytotoxicity and interferon-γ secretion are initiated by ITAM-dependent and -independent as well as LAT/NTAL-dependent and -independent pathways. The role of these various signaling circuits depends on the target cell as well as on the activation status of the NK cell. The multiplicity and the plasticity of the pathways that initiate NK cell effector functions contrast with the situation in T cells and B cells and provide an explanation for the resiliency of NK cell effector functions to various pharmacologic inhibitors and genetic mutations in signaling molecules.

Abstract 26: IL-17 Causes Hypertension, Reduced Fetal Weight And Natural Killer Cell Activation In The Absence Of T Cells

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Sarah J Fitzgerald ◽  
James Hogg ◽  
Evangeline Deer ◽  
Nathan Campbell ◽  
Owen Herrock ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Rat Model ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Interleukin 17 ◽  
Sprague Dawley ◽  
Th Cells ◽  
Atp Production

Preeclampsia (PE) is characterized by new onset hypertension (HTN), intrauterine growth restriction (IUGR), multi-organ dysfunction, and is associated with increased inflammatory cytokines, such as interleukin 17 (IL-17). More recent studies demonstrate a role for mitochondrial (mt) dysfunction/mtROS in the pathogenesis of PE. Although we have shown T helper cells from a rat model of PE cause HTN and mt dysfunction the causative factors for mt dysfunction are still being identified. In addition, we have shown that IL-17 cause HTN, IUGR and activate natural killer (NK) cells, and cause mt dysfunction in pregnant Sprague Dawley rats. However, in our previous studies we couldn’t differentiate the effect of activated TH cells versus IL-17 to cause these characteristics of PE. The athymic nude rat model lacks mature T cells but does have other components of the immune system, and will thus allow us to examine the role of IL-17 in the absence of TH cells in the pathophysiology of PE. We hypothesize that in the absence of T cells IL-17 induces HTN, NK cell activation and IUGR which is associated with renal and placental mt dysfunction during pregnancy. To test our hypothesis, IL-17 (150 pg/day) was infused via osmotic minipumps inserted on gestation day (GD) 14. Blood pressure (MAP) and mt function were measured on GD19 and were compared to untreated pregnant (NP) athymic nude rats. In response to IL-17; MAP increased from 95±4mmHg in NP(n=6) to 115±2 in NP+IL-17(n=6) (p<0.001); pup weight decreased from 1.46±0.2 g in NP (n=6) to 0.98±0.07g in NP+IL-17 (n=6) (p<0.05); NK cell activation increased from 0±0 %lymphocytes in NP (n=3) to 0.4±0.1% lymphocytes in NP+IL-17 rats (n=6). Interestingly, placental mtROS reduced 54% fold compared to NP and renal mtROS reduced 51.2% compared to NP. ATP production increased from 15.53±1.6 pmol of O2/sec/mg in NP (n=3) to 105.5±91 pmol of O2/sec/mg in NP+IL-17 (n=3) in the placenta, and from 1196±460 pmol of O2/sec/mg in NP (n=4) to 2016±951 pmol of O2/sec/mg NP+IL17 (n=4) in the kidney. These results show that although IL-17 induces HTN, IUGR, and NK cell activation independent of T cells, T cells are necessary for reduced mitochondrial function observed in PE and in rat models of placental ischemia.

scholarly journals Natural Killer Cells: Potential Biomarkers and Therapeutic Target in Autoimmune Diseases?

2021 ◽  
Vol 12 ◽  
Author(s):  
Elena Gianchecchi ◽  
Domenico V. Delfino ◽  
Alessandra Fierabracci
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Diseases ◽  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell

Autoimmune diseases recognize a multifactorial pathogenesis, although the exact mechanism responsible for their onset remains to be fully elucidated. Over the past few years, the role of natural killer (NK) cells in shaping immune responses has been highlighted even though their involvement is profoundly linked to the subpopulation involved and to the site where such interaction takes place. The aberrant number and functionality of NK cells have been reported in several different autoimmune disorders. In the present review, we report the most recent findings regarding the involvement of NK cells in both systemic and organ-specific autoimmune diseases, including type 1 diabetes (T1D), primary biliary cholangitis (PBC), systemic sclerosis, systemic lupus erythematosus (SLE), primary Sjögren syndrome, rheumatoid arthritis, and multiple sclerosis. In T1D, innate inflammation induces NK cell activation, disrupting the Treg function. In addition, certain genetic variants identified as risk factors for T1D influenced the activation of NK cells promoting their cytotoxic activity. The role of NK cells has also been demonstrated in the pathogenesis of PBC mediating direct or indirect biliary epithelial cell destruction. NK cell frequency and number were enhanced in both the peripheral blood and the liver of patients and associated with increased NK cell cytotoxic activity and perforin expression levels. NK cells were also involved in the perpetuation of disease through autoreactive CD4 T cell activation in the presence of antigen-presenting cells. In systemic sclerosis (SSc), in addition to phenotypic abnormalities, patients presented a reduction in CD56hi NK-cells. Moreover, NK cells presented a deficient killing activity. The influence of the activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) has been investigated in SSc and SLE susceptibility. Furthermore, autoantibodies to KIRs have been identified in different systemic autoimmune conditions. Because of its role in modulating the immune-mediated pathology, NK subpopulation could represent a potential marker for disease activity and target for therapeutic intervention.

scholarly journals Natural killer cell behavior in lymph nodes revealed by static and real-time imaging

2006 ◽  
Vol 203 (3) ◽  
pp. 619-631 ◽  
Author(s):  
Marc Bajénoff ◽  
Béatrice Breart ◽  
Alex Y.C. Huang ◽  
Hai Qi ◽  
Julie Cazareth ◽  
...  
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Leishmania Major ◽  
Nk Cell ◽  
Killer Cell

Natural killer (NK) cells promote dendritic cell (DC) maturation and influence T cell differentiation in vitro. To better understand the nature of the putative interactions among these cells in vivo during the early phases of an adaptive immune response, we have used immunohistochemical analysis and dynamic intravital imaging to study NK cell localization and behavior in lymph nodes (LNs) in the steady state and shortly after infection with Leishmania major. In the LNs of naive mice, NK cells reside in the medulla and the paracortex, where they closely associate with DCs. In contrast to T cells, intravital microscopy revealed that NK cells in the superficial regions of LNs were slowly motile and maintained their interactions with DCs over extended times in the presence or absence of immune-activating signals. L. major induced NK cells to secrete interferon-γ and to be recruited to the paracortex, where concomitant CD4 T cell activation occurred. Therefore, NK cells form a reactive but low mobile network in a strategic area of the LN where they can receive inflammatory signals, interact with DCs, and regulate colocalized T cell responses.

Differential regulation of virus-specific T-cell effector functions following activation by peptide or innate cytokines

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1179-1186 ◽  
Author(s):  
Carol Beadling ◽  
Mark K. Slifka
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Viral Infections ◽  
Interferon Γ ◽  
Interleukin 12 ◽  
Activated T Cells ◽  
Effector Functions

AbstractRobust CD8+ T-cell activation is vital for the recovery from many viral infections and is orchestrated via the integration of signals delivered through surface molecules, including the T-cell antigen receptors (TcRs) and cytokine receptors. Little is known about how virus-specific T cells interpret sequential or combined stimulation through these receptors, which must undoubtedly occur in vivo during antiviral immune responses. When measured in real time, peptide antigen and the cytokines, interleukin 12 (IL-12) and IL-18, independently regulate the on/off kinetics of protective (interferon γ, tumor necrosis factor α) and immunomodulatory (IL-2, CD40L) cytokine production by activated T cells and memory T cells. The remarkable differences in effector functions elicited by innate or adaptive signals (IL-12/ IL-18 or peptide, respectively) illustrate the complex and stringent regulation of cytokine expression by CD8+ T cells. Together, these results indicate how antiviral T cells incorporate multiple signals from their local microenvironment and tailor their cytokine responses accordingly.

scholarly journals Invariant natural killer T cell–natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5999-6010 ◽  
Author(s):  
Rachel D. Kuns ◽  
Edward S. Morris ◽  
Kelli P. A. MacDonald ◽  
Kate A. Markey ◽  
Helen M. Morris ◽  
...  
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Type I ◽  
Inkt Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. iNKT cells are activated through their T-cell receptors by glycolipid moieties (typically the α-galactosylceramide [α-GalCer] derivative KRN7000) presented within CD1d. We investigated the ability of modified α-GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well-established murine models of allogeneic stem cell transplantation. The highly potent and specific activation of all type I NKT cells with C20:2 failed to exacerbate and in most settings inhibited GVHD late after transplantation, whereas effects on GVL were variable. In contrast, the administration of KRN7000 induced hyperacute GVHD and early mortality in all models tested. Administration of KRN7000, but not C20:2, was found to result in downstream interleukin (IL)-12 and dendritic cell (DC)–dependent natural killer (NK)– and conventional T-cell activation. Specific depletion of host DCs, IL-12, or donor NK cells prevented this pathogenic response and the induction of hyperacute GVHD. These data demonstrate the ability of profound iNKT activation to modulate both the innate and adaptive immune response via the DC–NK-cell interaction and raise concern for the use of α-GalCer therapeutically to modulate GVHD and GVL effects.

scholarly journals Pivotal Role of KARAP/DAP12 Adaptor Molecule in the Natural Killer Cell–mediated Resistance to Murine Cytomegalovirus Infection

2002 ◽  
Vol 195 (7) ◽  
pp. 825-834 ◽  
Author(s):  
Hanna Sjölin ◽  
Elena Tomasello ◽  
Mehrdad Mousavi-Jazi ◽  
Armando Bartolazzi ◽  
Klas Kärre ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Interferon Γ ◽  
Mutant Mice ◽  
Murine Cytomegalovirus ◽  
Activating Receptors ◽  
And Function

Natural killer (NK) cells are major contributors to early defense against infections. Their effector functions are controlled by a balance between activating and inhibiting signals. To date, however, the involvement of NK cell activating receptors and signaling pathways in the defense against pathogens has not been extensively investigated. In mice, several NK cell activating receptors are coexpressed with and function through the immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecule KARAP/DAP12. Here, we have analyzed the role of KARAP/DAP12 in the early antiviral response to murine cytomegalovirus (MCMV). In KARAP/DAP12 mutant mice bearing a nonfunctional ITAM, we found a considerable increase in viral titers in the spleen (30–40-fold) and in the liver (2–5-fold). These effects were attributed to NK cells. The formation of hepatic inflammatory foci appeared similar in wild-type and mutant mice, but the latter more frequently developed severe hepatitis with large areas of focal necrosis. Moreover, the percentage of hepatic NK cells producing interferon γ was reduced by 56 ± 22% in the absence of a functional KARAP/DAP12. This is the first study that shows a crucial role for a particular activating signaling pathway, in this case the one induced through KARAP/DAP12, in the NK cell–mediated resistance to an infection. Our results are discussed in relation to recent reports demonstrating that innate resistance to MCMV requires the presence of NK cells expressing the KARAP/DAP12-associated receptor Ly49H.

scholarly journals Natural Killer Cell Dysfunction and Its Role in COVID-19

2020 ◽  
Vol 21 (17) ◽  
pp. 6351 ◽  
Author(s):  
Charmaine van Eeden ◽  
Lamia Khan ◽  
Mohammed S. Osman ◽  
Jan Willem Cohen Tervaert
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Natural Killer ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Clinical Manifestations ◽  
Effector Functions ◽  
Immune Balance ◽  
Cell Effector

When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this “perfect balance” is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.

scholarly journals Natural Killer Cell Activation Receptor NKp30 Oligomerization Depends on Its N-Glycosylation

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1998
Author(s):  
Ondřej Skořepa ◽  
Samuel Pazicky ◽  
Barbora Kalousková ◽  
Jan Bláha ◽  
Celeste Abreu ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Natural Killer ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Killer Cell ◽  
Structural Basis ◽  
Ligand Affinity ◽  
Activating Receptors ◽  
Successful Design

NKp30 is one of the main human natural killer (NK) cell activating receptors used in directed immunotherapy. The oligomerization of the NKp30 ligand binding domain depends on the length of the C-terminal stalk region, but our structural knowledge of NKp30 oligomerization and its role in signal transduction remains limited. Moreover, ligand binding of NKp30 is affected by the presence and type of N-glycosylation. In this study, we assessed whether NKp30 oligomerization depends on its N-glycosylation. Our results show that NKp30 forms oligomers when expressed in HEK293S GnTI− cell lines with simple N-glycans. However, NKp30 was detected only as monomers after enzymatic deglycosylation. Furthermore, we characterized the interaction between NKp30 and its best-studied cognate ligand, B7-H6, with respect to glycosylation and oligomerization, and we solved the crystal structure of this complex with glycosylated NKp30, revealing a new glycosylation-induced mode of NKp30 dimerization. Overall, this study provides new insights into the structural basis of NKp30 oligomerization and explains how the stalk region and glycosylation of NKp30 affect its ligand affinity. This furthers our understanding of the molecular mechanisms involved in NK cell activation, which is crucial for the successful design of novel NK cell-based targeted immunotherapeutics.

SLP-76 Is Required for Optimal Natural Killer Cell Activation and Ly49 Receptor Acquisition

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 103-103
Author(s):  
Rebecca May ◽  
Taku Kambayashi
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
Nk Cells ◽  
Signaling Pathways ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Granule Exocytosis ◽  
Activating Receptors ◽  
Mild Defect

Abstract Abstract 103 Natural killer (NK) cells are innate immune cells that defend the host from intracellular pathogens and tumors. Regulation of NK cell activation involves the expression of activating receptors that are finely counterbalanced by inhibitory MHC class I-binding receptors (e.g., Ly49 family members), which allow NK cells to achieve self-tolerance. How the precise signaling pathways leading from activating receptors contribute to effector function and inhibitory receptor acquisition by NK cells are not well understood. Thus, we aimed to dissect the proximal signaling pathways downstream of the Ly49D activating receptor and focused our studies on SLP-76 (SH2 containing leukocyte protein of 76kD), an adaptor molecule which is important in mediating signals downstream of ITAM-containing activating receptors in a variety of hematopoietic cell types. When NK cells were activated through Ly49D, SLP-76 was phosphorylated and recruited to the plasma membrane. SLP-76 was required for optimal signal transduction through Ly49D as SLP-76 knockout (KO) NK cells exhibited diminished ERK (extracellular signal-regulated kinase) and Akt phosphorylation compared to wildtype (WT) NK cells. These biochemical defects correlated with decreased IFNγ and TNFα production, and granule exocytosis by SLP-76 KO NK cells compared to WT NK cells. Although NK cells from SLP-76 KO mice appeared developmentally mature based on expression of late maturation markers DX5 and CD11b, we noted a selective defect in the acquisition of Ly49 family member inhibitory and activating receptors in SLP-76 KO NK cells. Since the defective function of SLP-76 KO NK cells might be related to their perturbed development, SLP-76 was inducibly deleted in NK cells after full maturation. Such NK cells displayed normal Ly49 receptor expression but still exhibited defective IFNg production and granule exocytosis, suggesting that SLP-76 plays an important role in Ly49D-mediated NK cell function. We next explored the mechanisms by which SLP-76 relocalizes from the cytosol to the plasma membrane and is subsequently phosphorylated. As this process depends on membrane-resident LAT (linker of activation of T cells) family adaptor molecules (LAT1 and LAT2) in T cells and mast cells, we tested whether LAT1 and LAT2 were similarly crucial for SLP-76 function in NK cells. Like SLP-76 KO NK cells, LAT1/LAT2 double KO (DKO) NK cells displayed significant functional defects. Surprisingly, however, membrane recruitment and phosphorylation of SLP-76 were intact in LAT1/LAT2 DKO NK cells following Ly49D stimulation. Moreover, a SLP-76 mutant that is unable to bind to LAT1/LAT2 was also recruited to the plasma membrane following Ly49D stimulation. Together, these results point towards the existence of a novel alternative signaling pathway leading to SLP-76 activation in NK cells. This alternative pathway may be important during NK cell development, since LAT1/LAT2 DKO NK cells displayed only a mild defect in Ly49 receptor acquisition compared to SLP-76 KO NK cells, underscoring the significance of this LAT1/LAT2-independent pathway. Together, these results demonstrate a critical role for a LAT1/LAT2-dependent and independent pathway leading to SLP-76 in NK cell activation and development. Disclosures: No relevant conflicts of interest to declare.

IgG antiplatelet immunity is dependent on an early innate natural killer cell–derived interferon-γ response that is regulated by CD8+ T cells

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2705-2709 ◽  
Author(s):  
Ebrahim Sayeh ◽  
Katherine Sterling ◽  
Edwin Speck ◽  
John Freedman ◽  
John W. Semple
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Interferon Γ ◽  
Wild Type ◽  
T Helper 2 ◽  
Ifn Γ ◽  
Platelet Transfusions

Abstract The mechanisms responsible for immunoglobulin G (IgG) immunity against allogeneic platelets are poorly understood. We studied the role that murine recipient CD8+ T and natural killer (NK) cells play in immunity against allogeneic platelets. BALB/c mice were depleted of the cells by cell-specific antibodies, transfused weekly with platelets from C57BL/6 mice, and serum IgG antidonor antibodies were measured by flow cytometry. While allogeneic platelet transfusions into wild-type recipients stimulated IgG antidonor antibodies in all mice by the fifth transfusion, CD8-depleted mice had significantly (P &lt; .001) enhanced antibody production. Isotype analysis revealed that CD8+ T cells suppressed T-helper 2 (Th2)-associated IgG1 but enhanced Th1-associated IgG2a. Compared with wild-type mice, platelet transfusions into CD8-depleted mice stimulated enhanced intracellular interferon (IFN)-γ production by CD4- lymphocytes within 24 hours after the first transfusion. The early IFN-γ response correlated with nitric oxide-dependent splenic cytotoxicity (P &lt; .001). In asialo ganglioside monosialic acid 1 (GM1)-depleted mice transfused with allogeneic platelets, the IFN-γ production, splenic cytotoxicity, and IgG antidonor antibody response were significantly suppressed. These results demonstrate that IgG antiplatelet immunity is dependent on an early NK cell-derived IFN-γ response that is negatively regulated by CD8+ T cells and suggest that targeting innate NK cell responses may significantly reduce platelet alloimmunization. (Blood. 2004;103:2705-2709)

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