scholarly journals NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules.

1994 ◽  
Vol 180 (2) ◽  
pp. 537-543 ◽  
Author(s):  
V Litwin ◽  
J Gumperz ◽  
P Parham ◽  
J H Phillips ◽  
L L Lanier
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Clone ◽  
Killer Cell ◽  
Cell Receptor ◽  
Target Cells ◽  
Multiple Alleles ◽  
Barr Virus ◽  
Cell Clones

Natural killer (NK) cells kill normal and transformed hematopoietic cells that lack expression of major histocompatibility complex (MHC) class I antigens. Lysis of HLA-negative Epstein Barr virus-transformed B lymphoblastoid cell lines (B-LCL) by human NK cell clones can be inhibited by transfection of the target cells with certain HLA-A, -B, or -C alleles. NK cell clones established from an individual demonstrate clonal heterogeneity in HLA recognition and a single NK clone can recognize multiple alleles. We describe a potential human NK cell receptor (NKB1) for certain HLA-B alleles (e.g., HLA-B*5101 and-B*5801) identified by the mAb DX9. NKB1 is a 70-kD glycoprotein that is expressed on a subset of NK cells and NK cell clones. DX9 monoclonal antibody (mAb) specifically inhibits the interaction between NK cell clones and B-LCL targets transfected with certain HLA-B alleles, but does not affect recognition of HLA-A or HLA-C antigens. An individual NK cell clone can independently recognize B-LCL targets transfected with HLA-B or HLA-C antigens; however, DX9 mAb only affects interaction with transfectants expressing certain HLA-B alleles. These findings demonstrate the existence of NK cell receptors involved in the recognition of HLA-B and imply the presence of multiple receptors for MHC on an individual NK clone.

scholarly journals The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor.

1995 ◽  
Vol 181 (3) ◽  
pp. 1133-1144 ◽  
Author(s):  
J E Gumperz ◽  
V Litwin ◽  
J H Phillips ◽  
L L Lanier ◽  
P Parham
Keyword(s):  
Monoclonal Antibody ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Inhibitory Effect ◽  
Glycosylation Site ◽  
Class I ◽  
Target Cells ◽  
Cell Clones

Although inhibition of natural killer (NK) cell-mediated lysis by the class I HLA molecules of target cells is an established phenomenon, knowledge of the features of class I molecules which induce this effect remains rudimentary. Using class I alleles HLA-B*1502 and B*1513 which differ only at residues 77-83 which define the Bw4 and Bw6 serological epitopes, we tested the hypothesis that the presence of the Bw4 epitope on class I molecules determines recognition by NKB1+ NK cells. HLA-B*1513 possesses the Bw4 epitope, whereas B*1502 has the Bw6 epitope. Lysis by NKB1+ NK cell clones of transfected target cells expressing B*1513 as the only HLA-A, -B, or -C molecule was inhibited, whereas killing of transfectants expressing B*1502 was not. Addition of an an anti-NKB1 monoclonal antibody reconstituted lysis of the targets expressing B*1513, but did not affect killing of targets bearing B*1502. The inhibitory effect of B*1513 could be similarly prevented by the addition of an anti-class I monoclonal antibody. These results show that the presence of the Bw4 epitope influences recognition of HLA-B molecules by NK cells that express NKB1, and suggest that the NKB1 molecule may act as a receptor for Bw4+ HLA-B alleles. Sequences outside of the Bw4 region must also affect recognition by NKB1+ NK cells, because lysis of transfectants expressing HLA-A*2403 or A*2501, which possess the Bw4 epitope but are in other ways substantially different from HLA-B molecules, was not increased by addition of the anti-NKB1 antibody. Asparagine 86, the single site of N-linked glycosylation on class I molecules, is in close proximity to the Bw4/Bw6 region. The glycosylation site of the Bw4-positive molecule B*5801 was mutated, and the mutant molecules tested for inhibition of NKB1+ NK cells. Inhibition that could be reversed by addition of the anti-NKB1 monoclonal antibody was observed, showing the presence of the carbohydrate moiety is not essential for class I recognition by NKB1+ NK cell clones.

scholarly journals NKG2A Complexed with CD94 Defines a Novel Inhibitory Natural Killer Cell Receptor

1997 ◽  
Vol 185 (4) ◽  
pp. 795-800 ◽  
Author(s):  
Andrew G. Brooks ◽  
Phillip E. Posch ◽  
Christopher J. Scorzelli ◽  
Francisco Borrego ◽  
John E. Coligan
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Protein S ◽  
Cell Receptor ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Cell Clones

CD94 is a C-type lectin expressed by natural killer (NK) cells and a subset of T cells. Blocking studies using anti-CD94 mAbs have suggested that it is a receptor for human leukocyte antigen class I molecules. CD94 has recently been shown to be a 26-kD protein covalently associated with an unidentified 43-kD protein(s). This report shows that NKG2A, a 43-kD protein, is covalently associated with CD94 on the surface of NK cells. Cell surface expression of NKG2A is dependent on the association with CD94 as glycosylation patterns characteristic of mature proteins are found only in NKG2A that is associated with CD94. Analysis of NK cell clones showed that NKG2A was expressed in all NK cell clones whose CD16-dependent killing was inhibited by cross-linking CD94. The induction of an inhibitory signal is consistent with the presence of two immunoreceptor tyrosine-based inhibitory motifs (V/LXYXXL) on the cytoplasmic domain of NKG2A. Similar motifs are found on Ly49 and killer cell inhibitory receptors, which also transmit negative signals to NK cells.

scholarly journals NKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1420
Author(s):  
Jagoda Siemaszko ◽  
Aleksandra Marzec-Przyszlak ◽  
Katarzyna Bogunia-Kubik
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Bacterial Infections ◽  
Killer Cell ◽  
Cell Receptor ◽  
Target Cells ◽  
Effector Cells ◽  
Stressed Cells ◽  
The Right ◽  
Nkg2d Receptor

Natural Killer (NK) cells are natural cytotoxic, effector cells of the innate immune system. They can recognize transformed or infected cells. NK cells are armed with a set of activating and inhibitory receptors which are able to bind to their ligands on target cells. The right balance between expression and activation of those receptors is fundamental for the proper functionality of NK cells. One of the best known activating receptors is NKG2D, a member of the CD94/NKG2 family. Due to a specific NKG2D binding with its eight different ligands, which are overexpressed in transformed, infected and stressed cells, NK cells are able to recognize and attack their targets. The NKG2D receptor has an enormous significance in various, autoimmune diseases, viral and bacterial infections as well as for transplantation outcomes and complications. This review focuses on the NKG2D receptor, the mechanism of its action, clinical relevance of its gene polymorphisms and a potential application in various clinical settings.

KLRL1, a novel killer cell lectinlike receptor, inhibits natural killer cell cytotoxicity

Blood ◽  
2004 ◽  
Vol 104 (9) ◽  
pp. 2858-2866 ◽  
Author(s):  
Yanmei Han ◽  
Minghui Zhang ◽  
Nan Li ◽  
Taoyong Chen ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
Target Cells ◽  
Lymphoid Tissues ◽  
Nk Cell Receptor ◽  
Human And Mouse

Abstract Natural killer (NK) cell inhibitory receptors play important roles in the regulation of target susceptibility to natural killing. Here, we report the molecular cloning and functional characterization of a novel NK cell receptor, KLRL1, from human and mouse dendritic cells. KLRL1 is a type II transmembrane protein with an immunoreceptor tyrosine-based inhibitory motif and a C-type lectinlike domain. The KLRL1 gene is located in the central region of the NK gene complex in both humans and mice, on human chromosome 12p13 and mouse chromosome 6F3, adjacent to the other KLR genes. KLRL1 is preferentially expressed in lymphoid tissues and immune cells, including NK cells, T cells, dendritic cells, and monocytes or macrophages. Western blot and fluorescence confocal microscopy analyses indicated that KLRL1 is a membrane-associated glycoprotein, which forms a heterodimer with an as yet unidentified partner. Human and mouse KLRL1 are both predicted to contain putative immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and immunoprecipitation experiments demonstrated that KLRL1 associates with the tyrosine phosphatases SHP-1 (SH2-domain-containing protein tyrosine phosphatase 1) and SHP-2. Consistent with its potential inhibitory function, pretreatment of target cells with human KLRL1-Fc fusion protein enhances NK-mediated cytotoxicity. Taken together, our results demonstrate that KLRL1 belongs to the KLR family and is a novel inhibitory NK cell receptor.

scholarly journals Deciphering the Immunological Phenomenon of Adaptive Natural Killer (NK) Cells and Cytomegalovirus (CMV)

2020 ◽  
Vol 21 (22) ◽  
pp. 8864
Author(s):  
Samantha Barnes ◽  
Ophelia Schilizzi ◽  
Katherine M. Audsley ◽  
Hannah V. Newnes ◽  
Bree Foley
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Cell Receptor ◽  
Vital Role ◽  
Immune Memory ◽  
Target Cells ◽  
Cytokines And Chemokines ◽  
Adaptive Immune Cells

Natural killer (NK) cells play a significant and vital role in the first line of defense against infection through their ability to target cells without prior sensitization. They also contribute significantly to the activation and recruitment of both innate and adaptive immune cells through the production of a range of cytokines and chemokines. In the context of cytomegalovirus (CMV) infection, NK cells and CMV have co-evolved side by side to employ several mechanisms to evade one another. However, during this co-evolution the discovery of a subset of long-lived NK cells with enhanced effector potential, increased antibody-dependent responses and the potential to mediate immune memory has revolutionized the field of NK cell biology. The ability of a virus to imprint on the NK cell receptor repertoire resulting in the expansion of diverse, highly functional NK cells to this day remains a significant immunological phenomenon that only occurs in the context of CMV. Here we review our current understanding of the development of these NK cells, commonly referred to as adaptive NK cells and their current role in transplantation, infection, vaccination and cancer immunotherapy to decipher the complex role of CMV in dictating NK cell functional fate.

Analysis of natural killer–cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease

Blood ◽  
2006 ◽  
Vol 108 (7) ◽  
pp. 2316-2323 ◽  
Author(s):  
Stefania Marcenaro ◽  
Federico Gallo ◽  
Stefania Martini ◽  
Alessandra Santoro ◽  
Gillian M. Griffiths ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cytokine Production ◽  
Nk Cell ◽  
Killer Cell ◽  
Target Cells ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Control Subjects ◽  
Healthy Control

Abstract Natural killer (NK) cells from patients with familial hemophagocytic lymphohistiocytosis because of PRF1 (FHL2, n = 5) or MUNC13-4 (FHL3, n = 8) mutations were cultured in IL-2 prior to their use in various functional assays. Here, we report on the surface CD107a expression as a novel rapid tool for identification of patients with Munc13-4 defect. On target interaction and degranulation, FHL3 NK cells displayed low levels of surface CD107a staining, in contrast to healthy control subjects or perforin-deficient NK cells. B-EBV cell lines and dendritic cell targets reveal the FHL3 NK-cell defect, whereas highly susceptible tumor targets were partially lysed by FHL3 NK cells expressing only trace amounts of Munc13-4 protein. Perforin-deficient NK cells were completely devoid of any ability to lyse target cells. Cytokine production induced by mAb-crosslinking of triggering receptors was comparable in patients and healthy control subjects. However, when cytokine production was induced by coculture with 721.221 B-EBV cells, FHL NK cells resulted in high producers, whereas control cells were almost ineffective. This could reflect survival versus elimination of B-EBV cells (ie, the source of NK-cell stimulation) in patients versus healthy control subjects, thus mimicking the pathophysiologic scenario of FHL.

scholarly journals Patients with a deficiency of natural killer cell activity lack the VEP13-positive lymphocyte subpopulation

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 65-70 ◽  
Author(s):  
HW Ziegler-Heitbrock ◽  
H Rumpold ◽  
D Kraft ◽  
C Wagenpfeil ◽  
R Munker ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Target Cells ◽  
Nk Cell Activity

Many patients with B-type chronic lymphocytic leukemia (CLL) exhibit a profound defect in their natural killer (NK) cell activity, the basis of which is still obscure. Hence, we analyzed the NK cells from peripheral blood samples from 11 patients with CLL for phenotype and function, after removal of the leukemic cells with a monoclonal antibody (BA-1) plus complement. Phenotypic analysis of these nonleukemic cells with monoclonal antibodies (MoAbs) against NK cells revealed that the CLL patients had higher percentages of HNK-1-positive cells (23.5% compared to controls with 14.7%). In contrast, VEP13- positive cells were absent or low in seven patients (0.8% compared to controls with 11.2%) and normal in four patients (10.5%). When testing NK cell activities against K562 or MOLT 4 target cells, patients with no or minimal numbers of VEP13-positive cells were found to be deficient, while patients with normal percentages of VEP13-positive cells had NK cell activity comparable to controls. Isolation by fluorescence-activated cell sorter of HNK-1-positive cells from patients lacking VEP13-positive cells and NK cell activity indicated that the majority of the HNK-1-positive cells in these patients had the large granular lymphocyte morphology that is characteristic of NK cells. Thus, the deficiency of NK cell activity in CLL patients appears to result from the absence of cells carrying the VEP13 marker.

scholarly journals HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1207-1214 ◽  
Author(s):  
Jeffrey Ward ◽  
Matthew Bonaparte ◽  
Jennifer Sacks ◽  
Jacqueline Guterman ◽  
Manuela Fogli ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Target Cells ◽  
Nk Cell Receptors ◽  
Infected Cells ◽  
Cytotoxic Responses

AbstractThe ability of natural killer (NK) cells to kill virus-infected cells depends on the presence of ligands for activation receptors on the target cells. We found the presence of few, if any, NKp30 and NK46 ligands on T cell blasts infected with HIV, although NKp44 ligands were found on infected cells. HIV does induce the NKG2D ligands ULBP-1, -2, and -3. These ligands are involved in triggering NK cells to kill autologous HIV-infected cells, because interfering with the interaction between NKG2D, but not NKp46, on NK cells and its ligands on HIV-infected cells drastically reduced the lysis of infected cells. Interfering with the binding of the NK-cell coreceptors NTB-A and 2B4 to their ligands also decreased destruction by NK cells. The coreceptor ligands, NTB-A and CD48, were also found to be down-regulated during the course of HIV infection. Thus, ligands for NK-cell receptors are modulated during the course of HIV infection, which may greatly alter NK cells' ability to kill the infected cells.

scholarly journals Glycosylation Affects Ligand Binding and Function of the Activating Natural Killer Cell Receptor 2B4 (CD244) Protein

2011 ◽  
Vol 286 (27) ◽  
pp. 24142-24149 ◽  
Author(s):  
Stefanie Margraf-Schönfeld ◽  
Carolin Böhm ◽  
Carsten Watzl
Keyword(s):  
Ligand Binding ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Negative Impact ◽  
Killer Cell ◽  
Target Cells ◽  
Functional Assay ◽  
Cell Responses

2B4 (CD244) is an important activating receptor for the regulation of natural killer (NK) cell responses. Here we show that 2B4 is heavily and differentially glycosylated in primary human NK cells and NK cell lines. The differential glycosylation could be attributed to sialic acid residues on N- and O-linked carbohydrates. Using a recombinant fusion protein of the extracellular domain of 2B4, we demonstrate that N-linked glycosylation of 2B4 is essential for the binding to its ligand CD48. In contrast, sialylation of 2B4 has a negative impact on ligand binding, as the interaction between 2B4 and CD48 is increased after the removal of sialic acids. This was confirmed in a functional assay system, where the desialylation of NK cells or the inhibition of O-linked glycosylation resulted in increased 2B4-mediated lysis of CD48-expressing tumor target cells. These data demonstrate that glycosylation has an important impact on 2B4-mediated NK cell function and suggest that regulated changes in glycosylation during NK cell development and activation might be involved in the regulation of NK cell responses.

scholarly journals Inhibitory Receptors Alter Natural Killer Cell Interactions with Target Cells Yet Allow Simultaneous Killing of Susceptible Targets

1999 ◽  
Vol 190 (7) ◽  
pp. 1005-1012 ◽  
Author(s):  
Mikael Eriksson ◽  
Guenther Leitz ◽  
Erik Fällman ◽  
Ove Axner ◽  
James C. Ryan ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Optical Tweezers ◽  
Target Cell ◽  
Nk Cell ◽  
Killer Cell ◽  
Class I ◽  
Target Cells ◽  
Inhibitory Receptors

Inhibitory receptors expressed on natural killer (NK) cells abrogate positive signals upon binding corresponding major histocompatibility complex (MHC) class I molecules on various target cells. By directly micromanipulating the effector–target cell encounter using an optical tweezers system which allowed temporal and spatial control, we demonstrate that Ly49–MHC class I interactions prevent characteristic cellular responses in NK cells upon binding to target cells. Furthermore, using this system, we directly demonstrate that an NK cell already bound to a resistant target cell may simultaneously bind and kill a susceptible target cell. Thus, although Ly49-mediated inhibitory signals can prevent many types of effector responses, they do not globally inhibit cellular function, but rather the inhibitory signal is spatially restricted towards resistant targets.

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