scholarly journals The Impact of Ly49-NK Cell-Dependent Recognition of MCMV Infection on Innate and Adaptive Immune Responses

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Michal Pyzik ◽  
Eve-Marie Gendron-Pontbriand ◽  
Silvia M. Vidal
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Cell Biology ◽  
Cell Activation ◽  
Nk Cell ◽  
Adaptive Immune Responses ◽  
Mcmv Infection ◽  
Adaptive Immune ◽  
Innate Lymphocytes ◽  
The Impact

Clinical and experimental data indicate that a subset of innate lymphocytes, natural killer (NK) cells, plays a crucial role in the response against herpesviruses, especially cytomegaloviruses (CMV). Indeed, in mice, NK cells, due to the expression of germline encoded Ly49 receptors, possess multiple mechanisms to recognize CMV infection. Classically, this results in NK cell activation and the destruction of the infected cells. More recently, however, this unique host-pathogen interaction has permitted the discovery of novel aspects of NK cell biology, implicating them in the regulation of adaptive immune responses as well as in the development of immunological memory. Here, we will concisely review the newly acquired evidence pertaining to NK cell Ly49-dependent recognition of MCMV-infected cell and the ensuing NK cell regulatory responses.

scholarly journals Dysregulation of Natural Killer Cells in Obesity

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 573 ◽  
Author(s):  
Donal O’Shea ◽  
Andrew E. Hogan
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Viral Infections ◽  
Nk Cell ◽  
Viral Immunity ◽  
Host Protection ◽  
Cell Functions ◽  
Innate Lymphocytes ◽  
The Impact

Natural killer (NK) cells are a population of lymphocytes which classically form part of the innate immune system. They are defined as innate lymphocytes, due to their ability to kill infected or transformed cells without prior activation. In addition to their cytotoxic abilities, NK cells are also rapid producers of inflammatory cytokines such as interferon gamma (IFN-γ) and are therefore a critical component of early immune responses. Due to these unique abilities, NK cells are a very important component of host protection, especially anti-tumour and anti-viral immunity. Obesity is a worldwide epidemic, with over 600 million adults and 124 million children now classified as obese. It is well established that individuals who are obese are at a higher risk of many acute and chronic conditions, including cancer and viral infections. Over the past 10 years, many studies have investigated the impact of obesity on NK cell biology, detailing systemic dysregulation of NK cell functions. More recently, several studies have investigated the role of NK cells in the homeostasis of adipose tissue and the pathophysiology of obesity. In this review, we will discuss in detail these studies and focus on emerging data detailing the metabolic mechanisms altering NK cells in obesity.

scholarly journals Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection

2009 ◽  
Vol 206 (10) ◽  
pp. 2235-2251 ◽  
Author(s):  
Seung-Hwan Lee ◽  
Kwang-Sin Kim ◽  
Nassima Fodil-Cornu ◽  
Silvia M. Vidal ◽  
Christine A. Biron
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Viral Infection ◽  
Nk Cells ◽  
Cell Expansion ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Activating Receptors

Natural killer (NK) cells have the potential to deliver both direct antimicrobial effects and regulate adaptive immune responses, but NK cell yields have been reported to vary greatly during different viral infections. Activating receptors, including the Ly49H molecule recognizing mouse cytomegalovirus (MCMV), can stimulate NK cell expansion. To define Ly49H's role in supporting NK cell proliferation and maintenance under conditions of uncontrolled viral infection, experiments were performed in Ly49h−/−, perforin 1 (Prf1)−/−, and wild-type (wt) B6 mice. NK cell numbers were similar in uninfected mice, but relative to responses in MCMV-infected wt mice, NK cell yields declined in the absence of Ly49h and increased in the absence of Prf1, with high rates of proliferation and Ly49H expression on nearly all cells. The expansion was abolished in mice deficient for both Ly49h and Prf1 (Ly49h−/−Prf1−/−), and negative consequences for survival were revealed. The Ly49H-dependent protection mechanism delivered in the absence of Prf1 was a result of interleukin 10 production, by the sustained NK cells, to regulate the magnitude of CD8 T cell responses. Thus, the studies demonstrate a previously unappreciated critical role for activating receptors in keeping NK cells present during viral infection to regulate adaptive immune responses.

scholarly journals Targeting NK Cells to Enhance Melanoma Response to Immunotherapies

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1363
Author(s):  
Hansol Lee ◽  
Inês Pires Da Silva ◽  
Umaimainthan Palendira ◽  
Richard A. Scolyer ◽  
Georgina V. Long ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Nk Cells ◽  
Cell Biology ◽  
Cell Activation ◽  
Nk Cell ◽  
Antitumor Effects ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Nk Cell Receptors ◽  
Immunosuppressive Cells

Natural killer (NK) cells are a key component of an innate immune system. They are important not only in initiating, but also in augmenting adaptive immune responses. NK cell activation is mediated by a carefully orchestrated balance between the signals from inhibitory and activating NK cell receptors. NK cells are potent producers of proinflammatory cytokines and are also able to elicit strong antitumor responses through secretion of perforin and granzyme B. Tumors can develop many mechanisms to evade NK cell antitumor responses, such as upregulating ligands for inhibitory receptors, secreting anti-inflammatory cytokines and recruiting immunosuppressive cells. Enhancing NK cell responses will likely augment the effectiveness of immunotherapies, and strategies to accomplish this are currently being evaluated in clinical trials. A comprehensive understanding of NK cell biology will likely provide additional opportunities to further leverage the antitumor effects of NK cells. In this review, we therefore sought to highlight NK cell biology, tumor evasion of NK cells and clinical trials that target NK cells.

scholarly journals Killing the Invaders: NK Cell Impact in Tumors and Anti-Tumor Therapy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 595
Author(s):  
Martina Molgora ◽  
Victor S. Cortez ◽  
Marco Colonna
Keyword(s):  
Nk Cells ◽  
Cell Biology ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Tumor Therapy ◽  
Tumor Immunotherapy ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
The Impact

Natural Killer cells belong to group 1 innate lymphoid cells, which also includes ILC1s. NK/ILC1s are highly heterogeneous cell types showing distinct phenotypes across tissues and conditions. NK cells have long been described as innate lymphocytes able to directly and rapidly kill tumor cells without antigen-restriction. Different mechanisms were shown to modulate NK cell activation and tumor resistance, mainly based on cytokine stimulation and receptor–ligand interactions, and several strategies have been developed to target NK cells in tumor immunotherapy to promote NK cell function and overcome tumor evasion. The characterization of ILC1 distinct phenotype and function and the specific role in tumors still needs further investigation and will be essential to better understand the impact of innate lymphoid cells in tumors. Here, we review key aspects of NK cell biology that are relevant in tumor immune surveillance, emphasizing the most recent findings in the field. We describe the novel therapeutical strategies that have been developed in tumor immunotherapy targeting NK cells, and we summarize some recent findings related to NK cell/ILC1 transition in tumor models.

scholarly journals Chemokine Receptor Expression on Normal Blood CD56+NK-Cells Elucidates Cell Partners That Comigrate during the Innate and Adaptive Immune Responses and Identifies a Transitional NK-Cell Population

2015 ◽  
Vol 2015 ◽  
pp. 1-18 ◽  
Author(s):  
Margarida Lima ◽  
Magdalena Leander ◽  
Marlene Santos ◽  
Ana Helena Santos ◽  
Catarina Lau ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Chemokine Receptors ◽  
Nk Cell ◽  
Cxcr4 Expression ◽  
Receptor Expression ◽  
Normal Blood ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Cd56 Expression

Studies of chemokine receptors (CKR) in natural killer- (NK-) cells have already been published, but only a few gave detailed information on its differential expression on blood NK-cell subsets. We report on the expression of the inflammatory and homeostatic CKR on normal bloodCD56+lowCD16+andCD56+high  CD16-/+lowNK-cells. ConventionalCD56+lowandCD56+highNK-cells present in the normal PB do express CKR for inflammatory cytokines, although with different patternsCD56+lowNK-cells are mainly CXCR1/CXCR2+and CXCR3/CCR5−/+, whereas mostlyCD56+highNK-cells are CXCR1/CXCR2−and CXCR3/CCR5+. Both NK-cell subsets have variable CXCR4 expression and are CCR4−and CCR6−. The CKR repertoire of theCD56+lowNK-cells approaches to that of neutrophils, whereas the CKR repertoire of theCD56+highNK-cells mimics that of Th1+T cells, suggesting that these cells are prepared to migrate into inflamed tissues at different phases of the immune response. In addition, we describe a subpopulation of NK-cells with intermediate levels of CD56 expression, which we namedCD56+intNK-cells. These NK-cells are CXCR3/CCR5+, they have intermediate levels of expression of CD16, CD62L, CD94, and CD122, and they are CD57−and CD158a−. In view of their phenotypic features, we hypothesize that they correspond to a transitional stage, between the well-knownCD56+highandCD56+lowNK-cells populations.

scholarly journals Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5

2018 ◽  
Vol 116 (3) ◽  
pp. 988-996 ◽  
Author(s):  
Han Wang ◽  
Jianxun Qi ◽  
Shuijun Zhang ◽  
Yan Li ◽  
Shuguang Tan ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Complex Structure ◽  
Binding Mode ◽  
Adaptive Immune ◽  
Binding Interface ◽  
Nk Cell Receptors ◽  
D2 Domain ◽  
Hybrid Complex

Natural killer (NK) cells are important component of innate immunity and also contribute to activating and reshaping the adaptive immune responses. The functions of NK cells are modulated by multiple inhibitory and stimulatory receptors. Among these receptors, the activating receptor CD226 (DNAM-1) mediates NK cell activation via binding to its nectin-like (Necl) family ligand, CD155 (Necl-5). Here, we present a unique side-by-side arrangement pattern of two tandem immunoglobulin V-set (IgV) domains deriving from the ectodomains of both human CD226 (hCD226-ecto) and mouse CD226 (mCD226-ecto), which is substantially different from the conventional head-to-tail arrangement of other multiple Ig-like domain molecules. The hybrid complex structure of mCD226-ecto binding to the first domain of human CD155 (hCD155-D1) reveals a conserved binding interface with the first domain of CD226 (D1), whereas the second domain of CD226 (D2) both provides structural supports for the unique architecture of CD226 and forms direct interactions with CD155. In the absence of the D2 domain, CD226-D1 exhibited substantially reduced binding efficacy to CD155. Collectively, these findings would broaden our knowledge of the interaction between NK cell receptors and the nectin/Necl family ligands, as well as provide molecular basis for the development of CD226-targeted antitumor immunotherapeutics.

CD154:CD40 Co-Stimulatory Blockade: A Novel Approach To Prevent Sensitization to Donor Alloantigens.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1273-1273
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Suzanne T. Ildstad
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
B Cell ◽  
Germinal Center ◽  
Cell Activation ◽  
Cell Tolerance ◽  
B Cell Activation ◽  
B Cell Tolerance ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

Abstract Introduction: Recipient sensitization is one of the most critical problems facing clinical transplantation. Allosensitized recipients often rapidly reject vascularized solid organ grafts as a result of preformed anti-donor antibody. Similarly, bone marrow transplantation for sickle cell disease and thalassemia is limited by sensitization from transfusion. A method to prevent sensitization would have a significant impact on transplant outcomes. Until recently, T cells were believed to be the primary effector cell in the induction of adaptive immune responses. We recently found that humoral immunity provides a dominant barrier in allosensitization to MHC antigens. B cell activation occurs through T-cell-dependent responses via signaling from the co-stimulatory molecule CD154 (on T cells) to its ligand CD40 (on B cells). Here, we examined whether blocking the costimulatory interaction between T and B cells during exposure to alloantigen would prevent allosensitization. Materials and Methods: Mice deficient for CD154 molecule (CD154−/ −, H-2b), α β-TCR+ T cells (TCRβ −/ −, H-2b); or wild type B6 (H-2b) mice received allogeneic BALB/c (H-2d) skin grafts (SG) on day 0. Some B6 mice were also treated with anti-CD154 (day0 and day+3) and/or anti-α β-TCR mAb (day-3) peritransplant. Antibodies were detected by flow cytometry cross-match (FCM) assay and reported as mean fluorescence intensity (MFI). Results: CD154−/ − mice rejected primary BALB/c SG with a time course similar to normal B6 controls (12.4 ± 2.1 vs. 12.7 ± 2.4 days). TCRβ −/ − mice accepted SG permanently (>120 days). Notably, anti-donor antibody was not generated in either the CD154−/ − or TCRβ −/ − mice (MFI: 4.1 ± 0.1 and 4.2 ± 0.4) after SG compared with Ab in naïve serum (3.0±0.2). Sensitized B6 mice had significantly higher antibody titers (106.8 ± 35.1) 4 weeks after SG rejection. A second SG transplanted 5 to 7 weeks after the first graft was rejected at an accelerated rate (9.0 ± 0.8 days, P < 0.05) in the CD154−/ − mice, but no anti-donor MHC antibody was produced. Second grafts placed on TCRβ −/ − mice were accepted, as were the primary SG. In normal B6 recipients pretreated with anti-CD154 or anti-α β-TCR alone, SG survival was not significantly prolonged. The Ab titers were only slightly higher in mice treated with anti-CD154 (5.9±3.4; P>0.05) than in naïve mice, and significantly higher in mice treated with mAb anti-α β-TCR (45.1±25.6; P=0.03). The combined treatment with both mAbs resulted in complete abrogation of Ab production (4.2±0.9) and 70% of skin grafts survived >100 days. Germinal center formation, reflective of B cell activation, was completely disrupted in mice treated with anti-CD154 alone or combined with anti-α β-TCR. Conclusion: These results suggest that the CD40/CD154 co-stimulatory pathway is critically important in B cell activation to generate alloantibody. Notably, blocking molecular interactions between CD40/CD154 abrogated the generation of antibody and blocked germinal center formation, inducing B cell tolerance. The additional removal of recipient T cells in the context of co-stimulatory blockade resulted in the induction of T as well as B cell tolerance. These findings are the first demonstration that sensitization can be prevented through blockade of co-stimulatory interactions in the generation of adaptive immune responses and could have a significant impact on management of sensitized recipients in the clinic.

Engaging the NKG2D Receptor with a Novel Bispecific Protein (ULBP2-antiCD138) Activates NK Cells and Has Potent Antitumor Activity Against Human Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5157-5157
Author(s):  
Elke Pogge von Strandmann ◽  
Michael Hallek ◽  
Andreas Engert
Keyword(s):  
Multiple Myeloma ◽  
Immune Responses ◽  
Nk Cells ◽  
Clinical Investigation ◽  
Human Peripheral Blood ◽  
Malignant Cells ◽  
Adaptive Immune Responses ◽  
Nude Mouse Model ◽  
Ifn Gamma ◽  
Adaptive Immune

Abstract NK cells, a component of the innate immune system, attack virus-infected and malignant cells without prior antigen stimulation, mediate cellular cytotoxicity and produce cytokines such as interferon gamma (IFN-gamma) upon stimulation. There is growing evidence that NK cells also participate directly in adaptive immune responses, mainly by cross-talk with dendritic cells. One key factor responsible for the activation of innate and adaptive immune responses is NKG2D, a stimulatory receptor expressed on natural killer cells that binds to cellular ligands on malignant cells. Therefore we designed a recombinant NK receptor ligand (ULBP2) fused to an antibody (BB4) detecting the tumor antigen CD138 which is overexpressed on a variety of malignancies including multiple myeloma (MM). The major findings were that (1) ULBP2-BB4 bound both NK cells and tumor cells, (2) triggered NK-mediated cell lysis of CD138+ malignant cell lines and primary MM cells in the allogenic and autologous setting, (3) activated IFN-gamma secretion of NK cells exposed to immobilized protein, and (4) the co-therapy with ULBP-BB4 and human peripheral blood lymphocytes abrogated the tumor growth in a nude mouse model with subcutaneously growing MM cells. This is the first report on the design, expression, purification and functional pre-clinical investigation of a recombinant NKG2D ligand. The results suggest not only a potential clinical use of this novel construct in patients with MM, but might also offer an innovative therapy approach which is based on NKG2D engagement transferable to other malignancies.

Zebrafish Mast Cells Demonstrate Conserved Innate and Adaptive Immune Responses

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3559-3559
Author(s):  
Evelyn M Teh ◽  
Olga Hrytsenko ◽  
Bill Pohajdak ◽  
Xiao Wen ◽  
Tong-jun Lin ◽  
...  
Keyword(s):  
Mast Cells ◽  
Immune Responses ◽  
Imatinib Mesylate ◽  
Cell Biology ◽  
High Throughput Screening ◽  
Fluorescent Protein ◽  
Fluorescent Labeling ◽  
Adaptive Immune Responses ◽  
Hematopoietic Stem ◽  
Adaptive Immune

Abstract Mast cells (MCs) are multifunctional immune cells derived from hematopoietic stem cells that uniquely complete maturation where they take up residence, namely in tissues exposed to the external environment. These anatomic locations position them to play a critical primary regulatory role in eliciting both innate and adaptive immune responses. The zebrafish has emerged as a powerful new model system for studying infection and immunity owing to conserved cell biology, and ease of manipulation and phenotypic analysis due to ex-utero embryonic development. We were the first (Dobson et al., Blood 2008) to identify MCs in zebrafish gills and intestine and carboxypeptidase A5 (cpa5) as a developmental marker of both embryonic progenitors and mature MCs. Intraperitoneal injection of compound 48/80, a MC activator, results in MC degranulation and elevated plasma tryptase levels as measured by chromogenic assay. Interestingly, we found that imatinib mesylate (Gleevec), an inhibitor of the C-KIT receptor, appears to block this MC activation. Pathogenic activation of MCs can occur through various well-conserved Toll-like receptors. We have demonstrated evidence of these innate immune pathways in zebrafish by infection with heat-inactivated A. salmonicida and the fungal wall constituent, zymosan. Each of these infectious stimuli results in zebrafish MC degranulation observed by light microscopy and by increased plasma tryptase levels. Mammalian MCs are better known for adaptive immune responses mediated through IgE/FcεRI signaling. We are characterizing an analogous pathway in the zebrafish and have shown that zebrafish MCs sensitized with mouse anti-DNP IgE followed by injection of DNP-BSA respond by degranulation, seen both by electron microscopy and tryptase assay. Equally interesting is the recruitment of eosinophils observed following MC stimulation by mouse anti-DNP/DNP-BSA. We are currently evaluating whether ketotifen, a MC stabilizer can attenuate this response as seen in mammalian systems. Moreover, we are interested to see whether imatinib mesylate or other tyrosine kinase inhibitors may play a role in abrogating this response, on account of cross-talk between C-KIT and IgE signaling cascades in mammals. The importance of proper MC function has been demonstrated in humans as well as various animal models where dysregulation results in disorders such as allergy, autoimmunity and mastocytosis. Our studies effectively establish the zebrafish as a novel model for evaluating vertebrate MC responses, which will be further enhanced through the fluorescent labeling of zebrafish MCs. These transgenic lines expressing green fluorescent protein (GFP) under the zebrafish cpa5 or c-kit promoters are being generated and germline screening is currently underway. Ultimately, we will be able to exploit the zebrafish system as an in vivo platform for high-throughput screening of potential MC stabilizing/inhibiting agents, with a goal of identifying new effective therapeutic strategies for use in allergic, inflammatory, and malignant diseases.

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.

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