scholarly journals CD33 (Siglec-3) Inhibitory Function: Role in the NKG2D/DAP10 Activating Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Trinidad Hernández-Caselles ◽  
Rubén Corral-San Miguel ◽  
Antonio José Ruiz-Alcaraz ◽  
Pilar García-Peñarrubia
Keyword(s):  
Nk Cells ◽  
Innate Immune ◽  
Inhibitory Receptor ◽  
Inhibitory Function ◽  
Activating Receptors ◽  
Self Tolerance ◽  
Lower Extent ◽  
Low Cytotoxicity ◽  
High Cytotoxicity

CD33 (siglec-3), a well-known target in leukemia therapy, is an inhibitory sialoadhesin expressed in human leukocytes of the myeloid lineage and some lymphoid subsets, including NK cells. It may constitute a control mechanism of the innate immune system; nevertheless, its role as an inhibitory receptor remains elusive. Using human NK cells as a cellular model, we analyzed CD33 inhibitory function upon different activating receptors. In high-cytotoxicity NKL cells, CD33 displayed a prominent inhibition on cytotoxicity triggered by the activating receptors NKG2D and, in a lower extent, 2B4, whereas it did not inhibit NKp46-induced cytotoxicity. NKp46 was partially inhibited by CD33 only when low-cytotoxicity NKL cells were tested. CD33 triggering did not inhibit IFN-γsecretion, contrasting with ILT-2 and CD94/NKG2A inhibitory receptors that inhibited cytotoxicity and IFN-γsecretion induced by all activating receptors tested. CD33-mediated inhibition of NKG2D-induced triggering involved Vav1 dephosphorylation. Our results support the role of CD33 as an inhibitory receptor preferentially regulating the NKG2D/DAP10 cytotoxic signaling pathway, which could be involved in self-tolerance and tumor and infected cell recognition.

scholarly journals GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1802
Author(s):  
Nayoung Kim ◽  
Mi Yeon Kim ◽  
Woo Seon Choi ◽  
Eunbi Yi ◽  
Hyo Jung Lee ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Negative Regulator ◽  
Target Cells ◽  
Dependent Manner ◽  
Cell Functions ◽  
Cell Based Therapy ◽  
Activating Receptors ◽  
Gsk 3Β

Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.

scholarly journals CD69 Deficiency Enhances the Host Response to Vaccinia Virus Infection through Altered NK Cell Homeostasis

2016 ◽  
Vol 90 (14) ◽  
pp. 6464-6474 ◽  
Author(s):  
Laura Notario ◽  
Elisenda Alari-Pahissa ◽  
Antonio de Molina ◽  
Pilar Lauzurica
Keyword(s):  
Immune Response ◽  
Infection Control ◽  
Vaccinia Virus ◽  
Nk Cells ◽  
Natural Killer ◽  
Host Response ◽  
Nk Cell ◽  
Innate Immune ◽  
Cell Numbers

ABSTRACTDuring the host response to viral infection, the transmembrane CD69 protein is highly upregulated in all immune cells. We have studied the role of CD69 in the murine immune response to vaccinia virus (VACV) infection, and we report that the absence of CD69 enhances protection against VACV at both short and long times postinfection in immunocompetent and immunodeficient mice. Natural killer (NK) cells were implicated in the increased infection control, since the differences were greatly diminished when NK cells were depleted. This role of NK cells was not based on an altered NK cell reactivity, since CD69 did not affect the NK cell activation threshold in response to major histocompatibility complex class I NK cell targets or protein kinase C activation. Instead, NK cell numbers were increased in the spleen and peritoneum of CD69-deficient infected mice. That was not just secondary to better infection control in CD69-deficient mice, since NK cell numbers in the spleens and the blood of uninfected CD69−/−mice were already augmented. CD69-deficient NK cells from infected mice did not have an altered proliferation capacity. However, a lower spontaneous cell death rate was observed for CD69−/−lymphocytes. Thus, our results suggest that CD69 limits the innate immune response to VACV infection at least in part through cell homeostatic survival.IMPORTANCEWe show that increased natural killer (NK) cell numbers augment the host response and survival after infection with vaccinia virus. This phenotype is found in the absence of CD69 in immunocompetent and immunodeficient hosts. As part of the innate immune system, NK lymphocytes are activated and participate in the defense against infection. Several studies have focused on the contribution of NK cells to protection against infection with vaccinia virus. In this study, it was demonstrated that the augmented early NK cell response in the absence of CD69 is responsible for the increased protection seen during infection with vaccinia virus even at late times of infection. This work indicates that the CD69 molecule may be a target of therapy to augment the response to poxvirus infection.

Role of CTLA4 A49G polymorphism in systemic lupus erythematosus and its geographical distribution

2019 ◽  
Vol 72 (10) ◽  
pp. 659-662 ◽  
Author(s):  
Vikas Kailashiya ◽  
Hanjabam Barun Sharma ◽  
Jyotsna Kailashiya
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Geographical Distribution ◽  
Lupus Erythematosus ◽  
Cytotoxic T Lymphocyte ◽  
Inhibitory Receptor ◽  
Systemic Lupus ◽  
Inhibitory Function ◽  
Ethnic Populations ◽  
Regulatory Lymphocytes

CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+ CD25+ T regulatory lymphocytes and transiently on activated CD4+ and CD8+ T lymphocytes. Its inhibitory function promotes long-lived anergy in immune cells and prevents autoimmunity. Therefore, it plays a crucial role in T cell-mediated autoimmunity, and thus in susceptibility to autoimmune diseases, including systemic lupus erythematosus (SLE). It is encoded by CTLA4 gene in humans. AtoG polymorphism at position +49 of CTLA4 gene is the only polymorphism which changes amino acid sequence from alanine to threonine in the leader sequence, which may affect the function of CTLA-4. Association of CTLA4 polymorphisms with SLE has been investigated in several reports in different ethnic populations from different countries, which have shown highly inconsistent findings. In this review, we have compiled previous studies which have reported the association of CTLA4 A49G polymorphism in SLE and its geographical distribution.

The role of IL-17 producing NK cells and other innate immune cells in poly(I:C) triggered exacerbation of experimental asthma

2016 ◽  
Author(s):  
Lars Lunding ◽  
Christina Vock ◽  
Sina Webering ◽  
Jochen Behrends ◽  
Christoph Hölscher ◽  
...  
Keyword(s):  
Nk Cells ◽  
Immune Cells ◽  
Innate Immune ◽  
Poly I:C ◽  
Innate Immune Cells

scholarly journals Modification Strategy of D-leucine Residue Addition on a Novel Peptide from Odorrana schmackeri, with Enhanced Bioactivity and In Vivo Efficacy

Toxins ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 611
Author(s):  
Aifang Yao ◽  
Yingxue Ma ◽  
Xiaoling Chen ◽  
Mei Zhou ◽  
Xinping Xi ◽  
...  
Keyword(s):  
Methicillin Resistant Staphylococcus Aureus ◽  
Therapeutic Potential ◽  
Wild Type ◽  
Anticancer Activities ◽  
Gram Positive Bacteria ◽  
Leucine Residue ◽  
Low Cytotoxicity ◽  
High Cytotoxicity

Brevinins are a well-characterised, frog-skin-derived, antimicrobial peptide (AMP) family, but their applications are limited by high cytotoxicity. In this study, a wild-type des-Leu2 brevinin peptide, named brevinin-1OS (B1OS), was identified from Odorrana schmackeri. To explore the significant role of the leucine residue at the second position, two variants, B1OS-L and B1OS-D-L, were designed by adding L-leucine and D-leucine residues at this site, respectively. The antibacterial and anticancer activities of B1OS-L and B1OS-D-L were around ten times stronger than the parent peptide. The activity of B1OS against the growth of Gram-positive bacteria was markedly enhanced after modification. Moreover, the leucine-modified products exerted in vivo therapeutic potential in an methicillin-resistant Staphylococcus aureus (MRSA)-infected waxworm model. Notably, the single substitution of D-leucine significantly increased the killing speed on lung cancer cells, where no viable H838 cells survived after 2 h of treatment with B1OS-D-L at 10 μM with low cytotoxicity on normal cells. Overall, our study suggested that the conserved leucine residue at the second position from the N-terminus is vital for optimising the dual antibacterial and anticancer activities of B1OS and proposed B1OS-D-L as an appealing therapeutic candidate for development.

scholarly journals Role of Natural Killer Cells in Multiple Sclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
A. A. Maghazachi
Keyword(s):  
Multiple Sclerosis ◽  
Nk Cells ◽  
Myelin Proteins ◽  
Target Cells ◽  
Autoimmune Encephalomyelitis ◽  
Cytokines And Chemokines ◽  
Activating Receptors ◽  
Great Discovery ◽  
Adaptive Immune Systems

Although the etiology of multiple sclerosis (MS) is not known, the consensus is that Th1 cells sensitized to myelin proteins in the periphery are recruited into the CNS and damage the myelin sheath. Natural killers (NK) are cells that spontaneously lyse tumor target cells and have immunoregulatory activity secreting multiple cytokines and chemokines, as well as interacting with cells of innate and adaptive immune systems. A great discovery in the field is the cloning of several inhibitory and activating receptors. Another important contribution is the discovery that these cells express many seven-transmembrane-spanning domain receptors which aid them in extravasations into injured tissues. Despite all this progress, the role of NK cells in autoimmune diseases including MS is still not quite clear. In this paper, I will summarize recent findings related to the effects of these cells in both MS and the animal model of experimental autoimmune encephalomyelitis (EAE). Hence, I will discuss the effects of drugs used to treat MS/EAE and then explain their effects on NK cells. These include anti-CD25 or daclizumab, interferon-β (IFN-β), natalizumab, glatiramer acetate (GA), and fingolimod (FTY720). Finally, I will explain the contribution of the recently discovered NK17/NK1 cells in MS disease.

scholarly journals Natural Killer Cells in Immunotherapy: Are We Nearly There?

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3139 ◽  
Author(s):  
Mireia Bachiller ◽  
Anthony M. Battram ◽  
Lorena Perez-Amill ◽  
Beatriz Martín-Antonio
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cancer Patients ◽  
Clinical Studies ◽  
Nk Cell ◽  
Innate Immune ◽  
Novel Studies ◽  
Cell Immunotherapy

Natural killer (NK) cells are potent anti-tumor and anti-microbial cells of our innate immune system. They are equipped with a vast array of receptors that recognize tumor cells and other pathogens. The innate immune activity of NK cells develops faster than the adaptive one performed by T cells, and studies suggest an important immunoregulatory role for each population against the other. The association, observed in acute myeloid leukemia patients receiving haploidentical killer-immunoglobulin-like-receptor-mismatched NK cells, with induction of complete remission was the determinant to begin an increasing number of clinical studies administering NK cells for the treatment of cancer patients. Unfortunately, even though transfused NK cells demonstrated safety, their observed efficacy was poor. In recent years, novel studies have emerged, combining NK cells with other immunotherapeutic agents, such as monoclonal antibodies, which might improve clinical efficacy. Moreover, genetically-modified NK cells aimed at arming NK cells with better efficacy and persistence have appeared as another option. Here, we review novel pre-clinical and clinical studies published in the last five years administering NK cells as a monotherapy and combined with other agents, and we also review chimeric antigen receptor-modified NK cells for the treatment of cancer patients. We then describe studies regarding the role of NK cells as anti-microbial effectors, as lessons that we could learn and apply in immunotherapy applications of NK cells; these studies highlight an important immunoregulatory role performed between T cells and NK cells that should be considered when designing immunotherapeutic strategies. Lastly, we highlight novel strategies that could be combined with NK cell immunotherapy to improve their targeting, activity, and persistence.

Natural Killer Cells Induce the Formation of Neutrophil Extracellular Traps (NETs) in Venous Thrombosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1424-1424
Author(s):  
François-René Bertin ◽  
Sandrine Laurance ◽  
Catherine Lemarie ◽  
Mark Blostein
Keyword(s):  
Venous Thrombosis ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Flow Restriction ◽  
Extracellular Traps

Abstract Thrombosis is considered to be a pathological deviation of physiologic hemostasis involving similar mechanisms. Interestingly, recent work demonstrates that innate immune cells promote venous thrombosis. Innate immune cells were shown to collaborate to induce the activation of the coagulation cascade and platelets. In particular, neutrophils contribute to venous thrombosis through the release of neutrophil extracellular traps (NETs). However, the mechanism triggering the formation of NETs during venous thrombosis remain unknown. Of interest, a study showed that IFNγ induced the formation of NETs. Thus, we investigated the role of IFNγ-producing cells in the development of thrombosis. We used mice lacking IFNγ, Tbet (the transcription factor regulating the expression of IFNγ) or wild type mice. Venous thrombosis was induced using the flow restriction model in the inferior vena cava , as has been previously published. In Tbet-/-, IFNγ-/- and WT mice, we show that the absence of Tbet or IFNγ decreases the formation of thrombi after venous thrombosis induction, suggesting that the Tbet+/IFNγ producing cells are required for the early development of venous thrombosis. Comparing the composition of the thrombi from Tbet-/-, IFNγ-/- and WT mice, we show that, in all mice, neutrophils are the main cellular component of thrombi followed by monocytes; however, the number of neutrophil extracellular traps (NETs) formed during thrombosis is significantly lower in Tbet-/- and IFNγ-/- mice. Furthermore, NET formation is also decreased in WT mice specifically depleted of IFNγ and increases in Tbet-/- and IFNγ-/- mice injected with recombinant IFNγ. In vitro, we show that stimulation of WT murine neutrophils with recombinant IFNγ triggers the formation of NETs demonstrating that Tbet and IFNγ are crucial for NET formation by neutrophils. Natural killer (NK) cells are the main producers of IFNγ . Thus, we investigated the role of NK cells in venous thrombosis induced by flow restriction. NK cells were specifically depleted with an antibody during the development of venous thrombosis. The absence of NK cells results in smaller thrombi suggesting that NK cells are required for early thrombus development. Additionally, depletion in NK cells results in decreased in-situ IFNγ production and decreased NET formation. To directly link NK cells to the formation of NETs, WT neutrophils were co-cultured with Tbet-/- and IFNγ-/- NK cells. We show that WT neutrophils release less NETs when cultured with Tbet-/- and IFNγ-/- NK cells as compared to WT NK cells. These data suggest that NK cells trigger the formation of NETs by neutrophils through the production of IFNγ. Hence, we demonstrate that, in a partial flow restriction model of venous thrombosis, Tbet and IFNγ are crucial for thrombus development by promoting the formation of NETs by neutrophils and that NK cells are key effector cells in this process. Disclosures Blostein: boehringer-ingelheim: Research Funding.

scholarly journals A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4416-4423 ◽  
Author(s):  
Nadine C. Fernandez ◽  
Emmanuel Treiner ◽  
Russell E. Vance ◽  
Amanda M. Jamieson ◽  
Suzanne Lemieux ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Class I ◽  
Inhibitory Receptor ◽  
Inhibitory Receptors ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecule ◽  
Self Tolerance

Abstract It is widely believed that self-tolerance of natural killer (NK) cells occurs because each NK cell expresses at least one inhibitory receptor specific for a host major histocompatibility complex (MHC) class I molecule. Here we report that some NK cells lack all known self-MHC–specific inhibitory receptors, yet are nevertheless self-tolerant. These NK cells exhibit a normal cell surface phenotype and some functional activity. However, they respond poorly to class I–deficient normal cells, tumor cells, or cross-linking of stimulatory receptors, suggesting that self-tolerance is established by dampening stimulatory signaling. Thus, self-tolerance of NK cells in normal animals can occur independently of MHC-mediated inhibition, and hyporesponsiveness plays a role in self-tolerance of NK cells, as also proposed for B and T cells.

Natural killer cell in the developing life

2015 ◽  
Vol 43 (1) ◽  
Author(s):  
Yen-Chang Lee ◽  
Syh-Jae Lin
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Killer Cell ◽  
Immune Defense ◽  
Innate Immune ◽  
First Line ◽  
Successful Pregnancy ◽  
Neonatal Stage

AbstractNatural killer (NK) cells that provide first-line innate immune reactions against virus-infected and tumor cells have different roles in different body sites and in different stages. From the beginning of life, NK cells participate in many aspects of development, especially in a successful pregnancy and a healthy neonatal stage. This article reviews recent advances regarding the role of NK cells in implantation, placentation and immune tolerance during pregnancy as well as in the neonatal immune defense. The interactions between NK cells and other immune cells in each developmental stage are discussed.

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