A discrete subset of epigenetically primed human NK cells mediates antigen-specific immune responses

2020 ◽  
Vol 5 (52) ◽  
pp. eaba6232 ◽  
Author(s):  
Victoria Stary ◽  
Ram Vinay Pandey ◽  
Johanna Strobl ◽  
Lisa Kleissl ◽  
Patrick Starlinger ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Subset ◽  
Cell Reactivity ◽  
Effector Site ◽  
Discrete Population ◽  
Specific Stimulation ◽  
Underlying Mechanisms ◽  
Genomic Regions

Adaptive features of natural killer (NK) cells have been reported in various species with different underlying mechanisms. It is unclear, however, which NK cell populations are capable of mounting antigen-specific recall responses and how such functions are regulated at the molecular level. Here, we identify and characterize a discrete population of CD49a+CD16− NK cells in the human liver that displays increased epigenetic potential to elicit memory responses and has the functional properties to exert antigen-specific immunity in the skin as an effector site. Integrated chromatin-based epigenetic and transcriptomic profiling revealed unique characteristics of hepatic CD49a+CD16− NK cells when compared with conventional CD49a−CD16+ NK cells, thereby defining active genomic regions and molecules underpinning distinct NK cell reactivity. In contrast to conventional NK cells, our results suggest that adaptive CD49a+CD16− NK cells are able to bypass the KIR receptor-ligand system upon antigen-specific stimulation. Furthermore, these cells were highly migratory toward chemokine gradients expressed in epicutaneous patch test lesions as an effector site of adaptive immune responses in the skin. These results define pathways operative in human antigen-specific adaptive NK cells and provide a roadmap for harnessing this NK cell subset for specific therapeutic or prophylactic vaccine strategies.

scholarly journals The Role of Natural Killer Cells in Autoimmune Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Umut Can Kucuksezer ◽  
Esin Aktas Cetin ◽  
Fehim Esen ◽  
Ilhan Tahrali ◽  
Nilgun Akdeniz ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Natural Killer ◽  
Lupus Erythematosus ◽  
Cell Biology ◽  
Nk Cell ◽  
Cell Activity ◽  
Cell Subset ◽  
Therapeutic Interventions ◽  
Surface Receptors

Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970’s. They are members of innate immunity and were initially defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don’t express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16+CD56dim subset is best-known by their cytotoxic functions, CD16-CD56bright NK cell subset produces a bunch of cytokines comparable to CD4+ T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet’s disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and “bridge” them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.

The Role of CD137 and Its Ligand in Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3130-3130
Author(s):  
Tina Baessler ◽  
Corina Buechele ◽  
Matthias Krusch ◽  
Benjamin J Schmiedel ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Immunity ◽  
Nk Cell ◽  
Cell Subset ◽  
Surrogate Marker ◽  
Lymphocytic Leukemia ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Cell Reactivity

Abstract Tumor immunosurveillance is dependent on the reciprocal interaction between tumor cells and anti-tumor immunity mediated e.g. by NK cells. This has led to the concept of tumor immunoediting, which incorporates the multitude of mechanisms underlying this dual tumor- and immune-sculpting interaction. Various members of the TNF/TNFR family modulate differentiation, proliferation, activation, and death of both tumor and immune effector cells. Very recently the TNFR family member CD137 has been shown to be induced on NK cells by Fc receptor triggering indicating that not only the Fab region but also the Fc part of a given antibody may be responsible for effects attributed to CD137 modulation (Lin et al., Blood2008, 112: 699). Thus we here studied the role of human CD137 and its cognate counterpart, the CD137 ligand (CD137L) in the interaction of CLL with NK cells. High levels of CD137L expression were detected on B-CLL cells in all investigated patients (n=40). Incubation of CLL cells in the presence of an immobilized CD137-Ig fusionprotein significantly induced the release of the immunoregulatory cytokine TNF demonstrating that CLL-expressed CD137L was capable to transduce bidirectional signals. Furthermore, we found that NK cells of CLL patients displayed substantial CD137 expression. While being absent on resting NK cells, CD137 expression was upregulated on the CD56dimCD16+ but not the CD56brightCD16− NK cell subset of healthy donors upon activation e.g. with IL-2 or IL-15. In addition, CD137 was also induced on NK cells after incubation in supernatants of PBMC of CLL patients. Surprisingly, disruption of CD137-CD137L interaction in cocultures of allogenic NK cells with patient CLL cells by blocking CD137 antibody caused a significant increase in NK cell cytotoxicity. The observed inhibitory effect of CD137L on NK cell reactivity was confirmed in cytotoxicity assays using CD137L-transfectants with mock-transfectants as control. Furthermore, blocking CD137-CD137L interaction also substantially enhanced Rituximab-induced antibody dependent cellular cytotoxicity in an allogenic setting. Importantly, CD137 blockade also substantially enhanced CD107a expression as a surrogate marker for granule mobilization on autologous NK cells within PBMC of B-CLL patients, and this effect was observed both in the absence and more pronounced in the presence of Rituximab. Thus, expression of functional CD137L by CLL cells impairs anti-tumor immunity by diminishing both direct and antibody-dependent cellular cytotoxicity of allogenic and autologous NK cells. Modulation of the CD137-CD137L system might therefore be a suitable therapeutic approach in strategies like antibody therapy which rely on a sufficient NK cell anti-tumor response.

scholarly journals Natural Killer Cells Are Present in Rag1−/− Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke

2021 ◽  
Author(s):  
Leoni Rolfes ◽  
Tobias Ruck ◽  
Christina David ◽  
Stine Mencl ◽  
Stefanie Bock ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Adoptive Transfer ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Subset ◽  
Neurological Deficits ◽  
In Vitro Assays ◽  
Experimental Stroke ◽  
Transfer Model

AbstractRag1−/− mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1−/− mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1nullIL2rgnull (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1−/− and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1−/− NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1−/− were comparable in number and function to those in WT mice. Rag1−/− mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.

scholarly journals Reduced frequency of cytotoxic CD56dim CD16+ NK cells leads to impaired antibody-dependent degranulation in EBV-positive classical Hodgkin lymphoma

2021 ◽  
Author(s):  
Elena Pánisová ◽  
Anna Lünemann ◽  
Simone Bürgler ◽  
Monika Kotur ◽  
Julien Lazarovici ◽  
...  
Keyword(s):  
Nk Cells ◽  
Hodgkin Lymphoma ◽  
Nk Cell ◽  
Cell Subset ◽  
Adjunctive Treatment ◽  
Classical Hodgkin Lymphoma ◽  
Barr Virus ◽  
Class 1 ◽  
Epstein Barr

AbstractAround 30–50% of classical Hodgkin lymphoma (cHL) cases in immunocompetent individuals from industrialized countries are associated with the B-lymphotropic Epstein-Barr virus (EBV). Although natural killer (NK) cells exhibit anti-viral and anti-tumoral functions, virtually nothing is known about quantitative and qualitative differences in NK cells in patients with EBV+ cHL vs. EBV- cHL. Here, we prospectively investigated 36 cHL patients without known immune suppression or overt immunodeficiency at diagnosis. All 10 EBV+ cHL patients and 25 out 26 EBV- cHL were seropositive for EBV antibodies, and EBV+ cHL patients presented with higher plasma EBV DNA levels compared to EBV- cHL patients. We show that the CD56dim CD16+ NK cell subset was decreased in frequency in EBV+ cHL patients compared to EBV- cHL patients. This quantitative deficiency translates into an impaired CD56dim NK cell mediated degranulation toward rituximab-coated HLA class 1 negative lymphoblastoid cells in EBV+ compared to EBV- cHL patients. We finally observed a trend to a decrease in the rituximab-associated degranulation and ADCC of in vitro expanded NK cells of EBV+ cHL compared to healthy controls. Our findings may impact on the design of adjunctive treatment targeting antibody-dependent cellular cytotoxicity in EBV+ cHL.

scholarly journals Direct Binding of Human NK Cell Natural Cytotoxicity Receptor NKp44 to the Surfaces of Mycobacteria and Other Bacteria

2008 ◽  
Vol 76 (4) ◽  
pp. 1719-1727 ◽  
Author(s):  
Semih Esin ◽  
Giovanna Batoni ◽  
Claudio Counoupas ◽  
Annarita Stringaro ◽  
Franca Lisa Brancatisano ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Subset ◽  
Surface Expression ◽  
Binding Assays ◽  
Igg Antibody ◽  
Direct Stimulation ◽  
Activating Receptors ◽  
Accessory Cells

ABSTRACT Our previous studies demonstrated that Mycobacterium bovis bacillus Calmette-Guérin (BCG) can directly interact with human NK cells and induce the proliferation, gamma interferon production, and cytotoxic activity of such cells without the need for accessory cells. Thus, the aim of the present study was to identify the putative receptor(s) responsible for the recognition of BCG by human NK cells and potentially involved in the activation of NK cells. To this end, we first investigated the surface expression of three NK cell-activating receptors belonging to the natural cytoxicity receptor (NCR) family on highly purified human NK cells upon in vitro direct stimulation with BCG. An induction of the surface expression of NKp44, but not of NKp30 or NKp46, was observed after 3 and 4 days of in vitro stimulation with live BCG. The NKp44 induction involved mainly a particular NK cell subset expressing the CD56 marker at high density, CD56bright. In order to establish whether NKp44 could directly bind to BCG, whole BCG cells were stained with soluble forms of the three NCRs chimeric for the human immunoglobulin G (IgG) Fc fragment (NKp30-Fc, NKp44-Fc, NKp46-Fc), followed by incubation with a phycoerythrin (PE)-conjugated goat anti-human IgG antibody. Analysis by flow cytometry of the complexes revealed a higher PE fluorescence intensity for BCG incubated with NKp44-Fc than for BCG incubated with NKp30-Fc, NKp46-Fc, or negative controls. The binding of NKp44-Fc to the BCG surface was confirmed with immunogold labeling using transmission electron microscopy, suggesting the presence of a putative ligand(s) for human NKp44 on the BCG cell wall. Similar binding assays performed on a number of gram-positive and gram-negative bacteria revealed a pattern of NKp44-Fc binding restricted to members of the genus Mycobacterium, to the mycobacterium-related species Nocardia farcinica, and to Pseudomonas aeruginosa. Altogether, the results obtained indicate, for the first time, that at least one member of the NCR family (NKp44) may be involved in the direct recognition of bacterial pathogens by human NK cells.

scholarly journals MITF induces escape from innate immunity in melanoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Luis Sánchez-del-Campo ◽  
Román Martí-Díaz ◽  
María F. Montenegro ◽  
Rebeca González-Guerrero ◽  
Trinidad Hernández-Caselles ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Nk Cells ◽  
Nk Cell ◽  
Luciferase Reporter ◽  
Damage Repair ◽  
Reporter Assays ◽  
Underlying Mechanisms ◽  
Nk Cytotoxicity

Abstract Background The application of immune-based therapies has revolutionized cancer treatment. Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood. In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair. Whether MITF also controls the immune response is unknown. Methods By using several mouse melanoma models, we examine the potential role of MITF to modulate the anti-melanoma immune response. ChIP-seq data analysis, ChIP-qPCR, CRISPR-Cas9 genome editing, and luciferase reporter assays were utilized to identify ADAM10 as a direct MITF target gene. Western blotting, confocal microscopy, flow cytometry, and natural killer (NK) cytotoxicity assays were used to determine the underlying mechanisms by which MITF-driven phenotypic plasticity modulates melanoma NK cell-mediated killing. Results Here we show that MITF regulates expression of ADAM10, a key sheddase that cleaves the MICA/B family of ligands for NK cells. By controlling melanoma recognition by NK-cells MITF thereby controls the melanoma response to the innate immune system. Consequently, while melanoma MITFLow cells can be effectively suppressed by NK-mediated killing, MITF-expressing cells escape NK cell surveillance. Conclusion Our results reveal how modulation of MITF activity can impact the anti-melanoma immune response with implications for the application of anti-melanoma immunotherapies.

scholarly journals The Ly-49D Receptor Activates Murine Natural Killer Cells

1996 ◽  
Vol 184 (6) ◽  
pp. 2119-2128 ◽  
Author(s):  
L.H. Mason ◽  
S.K. Anderson ◽  
W.M. Yokoyama ◽  
H.R.C. Smith ◽  
R. Winkler-Pickett ◽  
...  
Keyword(s):  
Gene Family ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Cell Subset ◽  
Class I ◽  
Target Cells ◽  
Color Flow ◽  
Functional Capabilities

Proteins encoded by members of the Ly-49 gene family are predominantly expressed on murine natural killer (NK) cells. Several members of this gene family have been demonstrated to inhibit NK cell lysis upon recognizing their class I ligands on target cells. In this report, we present data supporting that not all Ly-49 proteins inhibit NK cell function. Our laboratory has generated and characterized a monoclonal antibody (mAb) (12A8) that can be used to recognize the Ly-49D subset of murine NK cells. Transfection of Cos-7 cells with known members of the Ly-49 gene family revealed that 12A8 recognizes Ly-49D, but also cross-reacts with the Ly-49A protein on B6 NK cells. In addition, 12A8 demonstrates reactivity by both immunoprecipitation and two-color flow cytometry analysis with an NK cell subset that is distinct from those expressing Ly-49A, C, or G2. An Ly-49D+ subset of NK cells that did not express Ly49A, C, and G2 was isolated and examined for their functional capabilities. Tumor targets and concanovalin A (ConA) lymphoblasts from a variety of H2 haplotypes were examined for their susceptibility to lysis by Ly-49D+ NK cells. None of the major histocompatibility complex class I–bearing targets inhibited lysis of Ly-49D+ NK cells. More importantly, we demonstrate that the addition of mAb 12A8 to Ly-49D+ NK cells can augment lysis of FcγR+ target cells in a reverse antibody-dependent cellular cytotoxicity–type assay and induces apoptosis in Ly49D+ NK cells. Furthermore, the cytoplasmic domain of Ly-49D does not contain the V/IxYxxL immunoreceptor tyrosine-based inhibitory motif found in Ly-49A, C, or G2 that has been characterized in the human p58 killer inhibitory receptors. Therefore, Ly-49D is the first member of the Ly-49 family characterized as transmitting positive signals to NK cells, rather than inhibiting NK cell function.

scholarly journals Identification of a Porcine Liver EomeshighT-betlow NK Cell Subset That Resembles Human Liver Resident NK Cells

2019 ◽  
Vol 10 ◽  
Author(s):  
Steffi De Pelsmaeker ◽  
Sofie Denaeghel ◽  
Leen Hermans ◽  
Herman W. Favoreel
Keyword(s):  
Nk Cells ◽  
Human Liver ◽  
Nk Cell ◽  
Cell Subset ◽  
Porcine Liver

scholarly journals Hypoxia Modifies the Transcriptome of Human NK Cells, Modulates Their Immunoregulatory Profile, and Influences NK Cell Subset Migration

2018 ◽  
Vol 9 ◽  
Author(s):  
Monica Parodi ◽  
Federica Raggi ◽  
Davide Cangelosi ◽  
Claudia Manzini ◽  
Mirna Balsamo ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Subset

scholarly journals NK Cell Interaction With Platelets and Myeloid Cells in the Tumor Milieu

2020 ◽  
Vol 11 ◽  
Author(s):  
Stefanie Maurer ◽  
Lucas Ferrari de Andrade
Keyword(s):  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Germ Line ◽  
Immune Surveillance ◽  
Myeloid Cells ◽  
Cell Interaction ◽  
Underlying Mechanisms ◽  
Antigen Presenting ◽  
Surveillance Mechanism

Natural killer (NK) cells recognize and kill tumor cells via germ-line encoded receptors and polarized degranulation of cytotoxic molecules, respectively. As such, NK cells help to inhibit the development of cancers. The activating receptor NKG2D induces NK cell-mediated killing of metastasizing tumor cells by recognition of the stress-induced ligands MICA, MICB, and ULBP1-6. However, platelets enable escape from this immune surveillance mechanism by obstructing the interactions between NK cells and tumor cells or by cleaving the stress-induced ligands. It is also being increasingly appreciated that NK cells play additional roles in cancer immunity, including chemokine-mediated recruitment of antigen presenting cells in the tumor microenvironment that is followed by generation of adaptive immunity. However, the NK cell interplays with dendritic cells, and macrophages are extremely complex and involve molecular interactions via NKG2D and cytokine receptors. Specifically, NKG2D-mediated chronic interaction between NK cells and tumor-infiltrating macrophages causes immune suppression by differentiating NK cells toward a dysfunctional state. Here we discuss the underlying mechanisms of NK cell control by platelets and myeloid cells with focus on NKG2D and its ligands, and provide a timely perspective on how to harness these pathways with novel immunotherapeutic approaches.

Sign in / Sign up

Export Citation Format

Share Document