scholarly journals Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Alice Koenig ◽  
Chien-Chia Chen ◽  
Antoine Marçais ◽  
Thomas Barba ◽  
Virginie Mathias ◽  
...  
Keyword(s):  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
In Vitro Models ◽  
Endothelial Damage ◽  
Solid Organ ◽  
Vascular Rejection ◽  
Antibody Mediated Rejection ◽  
Missing Self

AbstractCurrent doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection.

scholarly journals SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell Activation via the HLA-E/NKG2A Pathway

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1975 ◽  
Author(s):  
Daria Bortolotti ◽  
Valentina Gentili ◽  
Sabrina Rizzo ◽  
Antonella Rotola ◽  
Roberta Rizzo
Keyword(s):  
Epithelial Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Spike Proteins

Natural killer cells are important in the control of viral infections. However, the role of NK cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has previously not been identified. Peripheral blood NK cells from SARS-CoV and SARS-CoV-2 naïve subjects were evaluated for their activation, degranulation, and interferon-gamma expression in the presence of SARS-CoV and SARS-CoV-2 spike proteins. K562 and lung epithelial cells were transfected with spike proteins and co-cultured with NK cells. The analysis was performed by flow cytometry and immune fluorescence. SARS-CoV and SARS-CoV-2 spike proteins did not alter NK cell activation in a K562 in vitro model. On the contrary, SARS-CoV-2 spike 1 protein (SP1) intracellular expression by lung epithelial cells resulted in NK cell-reduced degranulation. Further experiments revealed a concomitant induction of HLA-E expression on the surface of lung epithelial cells and the recognition of an SP1-derived HLA-E-binding peptide. Simultaneously, there was increased modulation of the inhibitory receptor NKG2A/CD94 on NK cells when SP1 was expressed in lung epithelial cells. We ruled out the GATA3 transcription factor as being responsible for HLA-E increased levels and HLA-E/NKG2A interaction as implicated in NK cell exhaustion. We show for the first time that NK cells are affected by SP1 expression in lung epithelial cells via HLA-E/NKG2A interaction. The resulting NK cells’ exhaustion might contribute to immunopathogenesis in SARS-CoV-2 infection.

scholarly journals NK-cell activation is associated with increased HIV transcriptional activity following allogeneic hematopoietic cell transplantation

2018 ◽  
Vol 2 (12) ◽  
pp. 1412-1416
Author(s):  
Louise E. Hogan ◽  
Christian Körner ◽  
Kristen Hobbs ◽  
Camille R. Simoneau ◽  
Cassandra Thanh ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcriptional Activity ◽  
Cell Activation ◽  
Hematopoietic Cell Transplantation ◽  
Nk Cell ◽  
Killer Cell ◽  
Graft Versus Host ◽  
Key Points ◽  
Hiv 1

Key Points Graft-versus-host effects may lead to HIV-1 reactivation and cell death of infected pre-HCT CD4+ T cells. Natural killer cell activation correlates with in vitro HIV-1 transcriptional activity in the setting of HCT.

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.

scholarly journals Natural Killer Anti-Tumor Activity Can Be Achieved by In Vitro Incubation With Heat-Killed BCG

2021 ◽  
Vol 12 ◽  
Author(s):  
Gloria Esteso ◽  
Nacho Aguiló ◽  
Esther Julián ◽  
Omodele Ashiru ◽  
Mei. M. Ho ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Myeloid Cell ◽  
Activation Effect ◽  
Aqueous Fraction ◽  
Cytokine Activation

Natural Killer cell receptors allow this heterogeneous immune population to efficiently fight both tumors and infection, so their use as immunotherapy agents is an active field of research. Cytokine activation, particularly by myeloid cell-derived IL15, can induce potent NK anti-tumor responses. While studying the mechanism of action of intravesical instillations of Bacille Calmette-Guérin (BCG) as therapy for patients with high risk non-muscle invasive bladder cancer, we showed that BCG can activate a cytotoxic CD56bright NK cell population which efficiently recognized bladder cancer cells. This pioneer immunotherapy provides an invaluable model to understand the role of different immune populations in tumor elimination. However, during the propagation of BCG worldwide a large number of genetically diverse BCG substrains developed. Here, we investigated the capacity of different BCG substrains to promote NK cell activation and confirmed that they were able to activate lymphocytes. Tice, Connaught and Moreau were the substrains with a stronger NK activation effect as measured by CD56 upregulation. Surprisingly, dead mycobacteria also stimulated PBMC cultures and we further demonstrate here that subcellular fractions of BCG-Tice, in the absence of live mycobacteria, could also induce an NK cell response. Lipids from BCG-Tice, but not from Mycobacterium bovis, stimulated NK cell activation and degranulation, whereas the aqueous fraction of either bacteria did not activate lymphocytes. However, delipidated BCG-Tice bacteria were able to activate effector cells (CD3+CD56+ and NK, CD3-CD56+). These data demonstrate that different components of mycobacteria can stimulate different immune subpopulations resulting in phenotypes suitable for cancer elimination.

scholarly journals Missing Self-Induced Activation of NK Cells Combines with Non-Complement-Fixing Donor-Specific Antibodies to Accelerate Kidney Transplant Loss in Chronic Antibody-Mediated Rejection

2020 ◽  
pp. ASN.2020040433
Author(s):  
Alice Koenig ◽  
Sarah Mezaache ◽  
Jasper Callemeyn ◽  
Thomas Barba ◽  
Virginie Mathias ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Nk Cells ◽  
Kidney Transplant ◽  
Cell Activation ◽  
Nk Cell ◽  
Antibody Mediated Rejection ◽  
Transplant Failure ◽  
Donor Specific Antibodies ◽  
Microvascular Inflammation ◽  
Missing Self

BackgroundBinding of donor-specific antibodies (DSAs) to kidney allograft endothelial cells that does not activate the classic complement cascade can trigger the recruitment of innate immune effectors, including NK cells. Activated NK cells contribute to microvascular inflammation leading to chronic antibody-mediated rejection (AMR). Recipient NK cells can also trigger antibody-independent microvascular inflammation by sensing the absence of self HLA class I molecules (“missing self”) on allograft endothelial cells. This translational study investigated whether the condition of missing self amplifies DSA-dependent NK cell activation to worsen chronic AMR.Methods and ResultsAmong 1682 kidney transplant recipients who underwent an allograft biopsy at Lyon University Hospital between 2004 and 2017, 135 fulfilled the diagnostic criteria for AMR and were enrolled in the study. Patients with complement-fixing DSAs identified by a positive C3d binding assay (n=73, 54%) had a higher risk of transplant failure (P=0.002). Among the remaining patients with complement-independent chronic AMR (n=62, 46%), those in whom missing self was identified through donor and recipient genotyping exhibited worse allograft survival (P=0.02). In multivariable analysis, only proteinuria (HR: 7.24; P=0.01) and the presence of missing self (HR: 3.57; P=0.04) were independent predictors for transplant failure following diagnosis of chronic AMR. Cocultures of human NK cells and endothelial cells confirmed that addition of missing self to DSA-induced NK cell activation increased endothelial damage.ConclusionsThe assessment of missing self at the time of diagnosis of chronic AMR identifies patients at higher risk for kidney transplant failure.

scholarly journals Cytomegalovirus immunoevasin reveals the physiological role of “missing self” recognition in natural killer cell dependent virus control in vivo

2010 ◽  
Vol 207 (12) ◽  
pp. 2663-2673 ◽  
Author(s):  
Marina Babić ◽  
Michal Pyzik ◽  
Biljana Zafirova ◽  
Maja Mitrović ◽  
Višnja Butorac ◽  
...  
Keyword(s):  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Physiological Role ◽  
Dependent Manner ◽  
Class I Mhc ◽  
Mhc I ◽  
Missing Self

Cytomegaloviruses (CMVs) are renowned for interfering with the immune system of their hosts. To sidestep antigen presentation and destruction by CD8+ T cells, these viruses reduce expression of major histocompatibility complex class I (MHC I) molecules. However, this process sensitizes the virus-infected cells to natural killer (NK) cell–mediated killing via the “missing self” axis. Mouse cytomegalovirus (MCMV) uses m152 and m06 encoded proteins to inhibit surface expression of MHC I molecules. In addition, it encodes another protein, m04, which forms complexes with MHC I and escorts them to the cell surface. This mechanism is believed to prevent NK cell activation and killing by restoring the “self” signature and allowing the engagement of inhibitory Ly49 receptors on NK cells. Here we show that MCMV lacking m04 was attenuated in an NK cell– and MHC I–dependent manner. NK cell–mediated control of the infection was dependent on the presence of NK cell subsets expressing different inhibitory Ly49 receptors. In addition to providing evidence for immunoevasion strategies used by CMVs to avoid NK cell control via the missing-self pathway, our study is the first to demonstrate that missing self–dependent NK cell activation is biologically relevant in the protection against viral infection in vivo.

Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3571-3578 ◽  
Author(s):  
Jérôme D. Coudert ◽  
Léonardo Scarpellino ◽  
Frédéric Gros ◽  
Eric Vivier ◽  
Werner Held
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Host Cells ◽  
Cross Tolerance ◽  
Self Recognition ◽  
Missing Self ◽  
Activation Pathways

Abstract NKG2D is a multisubunit activation receptor that allows natural killer (NK) cells to detect and eliminate stressed, infected, and transformed host cells. However, the chronic exposure of NK cells to cell-bound NKG2D ligands has been shown to impair NKG2D function both in vitro and in vivo. Here we have tested whether continuous NKG2D engagement selectively impacted NKG2D function or whether heterologous NK cell activation pathways were also affected. We found that sustained NKG2D engagement induced cross-tolerization of several unrelated NK cell activation receptors. We show that receptors that activate NK cells via the DAP12/KARAP and DAP10 signaling adaptors, such as murine NKG2D and Ly49D, cross-tolerize preferentially NK cell activation pathways that function independent of DAP10/12, such as antibody-dependent cell-mediated cytotoxicity and missing-self recognition. Conversely, DAP10/12-independent pathways are unable to cross-tolerize unrelated NK cell activation receptors such as NKG2D or Ly49D. These data define a class of NK cell activation receptors that can tolerize mature NK cells. The reversible suppression of the NK cells' cytolytic function probably reduces the NK cells' efficacy to control endogenous and exogenous stress yet may be needed to limit tissue damage.

scholarly journals WF10 Stimulates NK Cell Cytotoxicity by Increasing LFA-1-Mediated Adhesion to Tumor Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Louisa Kühne ◽  
Mathias Konstandin ◽  
Yvonne Samstag ◽  
Stefan Meuer ◽  
Thomas Giese ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Target Cells ◽  
Dependent Manner ◽  
Cell Cytotoxicity ◽  
Natural Killer Cell Cytotoxicity ◽  
Nk Cell Cytotoxicity

The redox-active chlorite-based drug WF10 (Immunokine) was shown to have modulatory effects on both the innate and adaptive immune systemin vitroandin vivo. Animal studies suggest that WF10 enhances immunity against tumors. One possible explanation for such an effect is that WF10 stimulates natural killer cell cytotoxicity against malignant cells. Here, we show that WF10 regulates human NK cell cytotoxicity in a time-dependent manner, following an S-shaped kinetic with an initial stimulation of activity followed by a decrease in activity relative to the untreated controls. WF10 does not activate NK cells on its own but co-stimulates NK cell activation mediated by different activating receptors. This is mediated by enhancing NK cell adhesion to target cells through promoting the activation of the integrin LFA-1. These data demonstrate a direct effect of WF10 on the cytotoxicity of human NK cells.

scholarly journals TGFβ Imprinting During Activation Promotes Natural Killer Cell Cytokine Hypersecretion

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 423 ◽  
Author(s):  
Jennifer Foltz ◽  
Jena Moseman ◽  
Aarohi Thakkar ◽  
Nitin Chakravarti ◽  
Dean Lee
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Transforming Growth Factor Beta ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Nk Cell ◽  
Killer Cell ◽  
Necrosis Factor Alpha ◽  
Cell Sensitivity

Transforming growth factor-beta (TGFβ) is a potent immunosuppressive cytokine that inhibits the anti-tumor responses of NK cells and T cells. However, the stimulation of natural killer (NK) cells with pro-inflammatory cytokines decreases NK cell sensitivity to TGFβ. Herein, we sought to determine if TGFβ imprinting (TGFβi) during NK cell activation and expansion would decrease NK cell sensitivity to TGFβ suppression. To this end, we demonstrate that the activation of NK cells during chronic IL-2 stimulation and TGFβi potently induces NK cell hypersecretion of interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) in response to tumor targets which persists for at least one month in vitro after the removal of TGFβ. TGFβi NK cell cytokine hypersecretion is induced following both cytokine and tumor activation. Further, TGFβi NK cells have a marked suppression of SMAD3 and T-bet which is associated with altered chromatin accessibility. In contrast to their heightened cytokine secretion, TGFβi NK cells downregulate several activating receptors, granzyme and perforin, and upregulate TRAIL, leading to cell-line-specific alterations in cytotoxicity. These findings may impact our understanding of how TGFβ affects NK cell development and anti-tumor function.

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