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 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 Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell–mediated lysis of myeloma

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1309-1317 ◽  
Author(s):  
Jumei Shi ◽  
Guido J. Tricot ◽  
Tarun K. Garg ◽  
Priyangi A. Malaviarachchi ◽  
Susann M. Szmania ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Expression ◽  
Class I ◽  
Cell Surface Expression ◽  
Significant Activity

AbstractHuman leukocyte antigen class I molecules expressed by tumor cells play a central role in the regulation of natural killer (NK) cell–mediated immune responses. The proteasome inhibitor bortezomib has demonstrated significant activity in multiple myeloma (MM). We hypothesized that treatment of MM with bortezomib results in the reduction of cell-surface expression of class I and thereby sensitizes MM to NK cell–mediated lysis. Here we report that bortezomib down-regulates class I in a time- and dose-dependent fashion on all MM cell lines and patient MM cells tested. Downregulation of class I can also be induced in vivo after a single dose of 1.0 mg/m2 bortezomib. Bortezomib significantly enhances the sensitivity of patient myeloma to allogeneic and autologous NK cell–mediated lysis. Further, the level of decrease in class I expression correlates with increased susceptibility to lysis by NK cells. Clinically relevant bortezomib concentrations do not affect NK-cell function. Our findings have clear therapeutic implications for MM and other NK cell–sensitive malignancies in the context of both allogeneic and autologous adoptively transferred NK cells.

Impact of β2 integrin deficiency on mouse natural killer cell development and function

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2874-2882 ◽  
Author(s):  
Karine Crozat ◽  
Céline Eidenschenk ◽  
Baptiste N. Jaeger ◽  
Philippe Krebs ◽  
Sophie Guia ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Surface Expression ◽  
Cell Maturation ◽  
Cell Surface Expression ◽  
Mcmv Infection ◽  
Β2 Integrin

Abstract Natural killer (NK) cells are innate immune cells that express members of the leukocyte β2 integrin family in humans and mice. These CD11/CD18 heterodimers play critical roles in leukocyte trafficking, immune synapse formation, and costimulation. The cell-surface expression of one of these integrins, CD11b/CD18, is also recognized as a major marker of mouse NK-cell maturation, but its function on NK cells has been largely ignored. Using N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated a mouse carrying an A → T transverse mutation in the Itgb2 gene, resulting in a mutation that prevented the cell-surface expression of CD18 and its associated CD11a, CD11b, and CD11c proteins. We show that β2 integrin–deficient NK cells have a hyporesponsive phenotype in vitro, and present an alteration of their in vivo developmental program characterized by a selective accumulation of c-kit+ cells. NK-cell missing-self recognition was partially altered in vivo, whereas the early immune response to mouse cytomegalovirus (MCMV) infection occurred normally in CD18-deficient mice. Therefore, β2 integrins are required for optimal NK-cell maturation, but this deficiency is partial and can be bypassed during MCMV infection, highlighting the robustness of antiviral protective responses.

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 Killer Cell Inhibitory Receptor Recognition of Human Leukocyte Antigen (HLA) Class I Blocks Formation of a pp36/PLC-γ Signaling Complex in Human Natural Killer (NK) Cells

1996 ◽  
Vol 184 (6) ◽  
pp. 2243-2250 ◽  
Author(s):  
Nicholas M. Valiante ◽  
Joseph H. Phillips ◽  
Lewis L. Lanier ◽  
Peter Parham
Keyword(s):  
Human Leukocyte Antigen ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Class I ◽  
Cell Cytotoxicity ◽  
Leukocyte Antigen ◽  
Nk Cell Cytotoxicity

The killer cell inhibitory receptors (KIR) of human natural killer (NK) cells recognize human leukocyte antigen class I molecules and inhibit NK cell cytotoxicity through their interaction with protein tyrosine phosphatases (PTP). Here, we report that KIR recognition of class I ligands inhibits distal signaling events and ultimately NK cell cytotoxicity by blocking the association of an adaptor protein (pp36) with phospholipase C-γ in NK cells. In addition, we demonstrate that pp36 can serve as a substrate in vitro for the KIR-associated PTP, PTP-1C (also called SHP-1), and that recognition of class I partially disrupts tyrosine phosphorylation of NK cell proteins, providing evidence for KIR-induced phosphatase activity.

scholarly journals p46, a Novel Natural Killer Cell–specific Surface Molecule That Mediates Cell Activation

1997 ◽  
Vol 186 (7) ◽  
pp. 1129-1136 ◽  
Author(s):  
Simona Sivori ◽  
Massimo Vitale ◽  
Luigia Morelli ◽  
Lorenza Sanseverino ◽  
Raffaella Augugliaro ◽  
...  
Keyword(s):  
Specific Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Cytolytic Activity ◽  
Surface Molecule ◽  
Limited Information ◽  
Cell Clones

Limited information is available on the surface molecules that are involved in natural killer (NK) cell triggering. In this study, we selected the BAB281 monoclonal antibody (mAb) on the basis of its ability to trigger NK-mediated target cell lysis. BAB281 identified a novel NK cell–specific surface molecule of 46 kD (p46) that is expressed by all resting or activated NK cells. Importantly, unlike the NK cell antigens identified so far, the expression of p46 was strictly confined to NK cells. Upon mAb-mediated cross-linking, p46 molecules induced strong cell triggering leading to [Ca2+]i increases, lymphokine production, and cytolytic activity both in resting NK cells and NK cell clones. The p46-mediated induction of Ca2+ increases or triggering of cytolytic activity was downregulated by the simultaneous engagement of inhibitory receptors including p58, p70, and CD94/NKG2A. Both the unique cellular distribution and functional capability of p46 molecules suggest a possible role in the mechanisms of non-major histocompatibility complex–restricted cytolysis mediated by human NK cells.

scholarly journals NKR-P1A is a target-specific receptor that activates natural killer cell cytotoxicity.

1995 ◽  
Vol 181 (5) ◽  
pp. 1911-1915 ◽  
Author(s):  
J C Ryan ◽  
E C Niemi ◽  
M C Nakamura ◽  
W E Seaman
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Receptor ◽  
Specific Receptor ◽  
Natural Killer Cell Cytotoxicity ◽  
Natural Killing ◽  
Inositol 1,4,5 Trisphosphate ◽  
Functional Features

NKR-P1A is a lectinlike surface molecule expressed on rat natural killer (NK) cells. NKR-P1A has structural and functional features of an activating NK cell receptor, but a requirement for NKR-P1A in target cell lysis has not been determined. To define the role of NKR-P1A in natural killing, we have generated a mutant of the rat NK cell line, RNK-16, lacking expression of all members of the NKR-P1 receptor family. Although these NKR-P1-deficient NK cells were able to kill many standard tumor targets, including YAC-1, they were selectively deficient in the lysis of IC-21 macrophage, B-16 melanoma, and C1498 lymphoma targets. Reexpression of a single member of the NKR-P1 family, NKR-P1A, on mutant cells restored lysis of IC-21, and killing of IC-21 targets through rat NKR-P1A was completely blocked by F(ab')2 anti-NKR-P1A. Reexpression of NKR-P1A also restored transmembrane signaling to IC-21, as assessed by the generation of inositol-1,4,5-trisphosphate. The generation of inositol-1,4,5-trisphosphate was also restored in response to B-16 targets, but both B-16 and C1498 cells remained resistant to lysis, indicating that other NK cell molecules, perhaps within the NKR-P1 family, are required for the efficient killing of these tumors. These results are the first to demonstrate that NKR-P1A is a target-specific receptor that activates natural killing.

scholarly journals Modulation of NKG2D, NKp46, and Ly49C/I facilitates natural killer cell-mediated control of lung cancer

2018 ◽  
Vol 115 (46) ◽  
pp. 11808-11813 ◽  
Author(s):  
Lei Shi ◽  
Kang Li ◽  
Yizhan Guo ◽  
Anirban Banerjee ◽  
Qing Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Surface Expression ◽  
Intrinsic Factors ◽  
Immunologic Control

Natural killer (NK) cells play a critical role in controlling malignancies. Susceptibility or resistance to lung cancer, for example, specifically depends on NK cell function. Nevertheless, intrinsic factors that control NK cell-mediated clearance of lung cancer are unknown. Here we report that NK cells exposed to exogenous major histocompatibility class I (MHCI) provide a significant immunologic barrier to the growth and progression of malignancy. Clearance of lung cancer is facilitated by up-regulation of NKG2D, NKp46, and other activating receptors upon exposure to environmental MHCI. Surface expression of the inhibitory receptor Ly49C/I, on the other hand, is down-regulated upon exposure to tumor-bearing tissue. We thus demonstrate that NK cells exhibit dynamic plasticity in surface expression of both activating and inhibitory receptors based on the environmental context. Our data suggest that altering the activation state of NK cells may contribute to immunologic control of lung and possibly other cancers.

scholarly journals The Direct Influence of Cytomegalovirus Lysate on the Natural Killer Cell Receptor Repertoire

2021 ◽  
Author(s):  
Saeede Soleimanian ◽  
Ramin Yaghobi ◽  
Mohammad Hossein Karimi ◽  
Bita Geramizadeh ◽  
Jamshid Roozbeh
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Receptor ◽  
Direct Influence ◽  
Receptor Repertoire ◽  
Adaptive Capabilities ◽  
Nk Cell Receptor ◽  
Cell Receptor Repertoire

Natural killer (NK) cells are essential for controlling certain viral infections, including cytomegalovirus (CMV). In particular, the importance of NK cells in the context of CMV infection is underscored by the adaptive capabilities of these cells. Evidence suggests that some viruses can directly interfere with NK cell compartments and their activation and lead to shape-shifting the NK cell receptor repertoire. Still, it remains unknown whether the CMV can interact with NK cells without intermediaries. Here, we examined whether the direct effects of CMV lysate alter phenotypical properties of NK cells. To investigate this issue, NK cells were isolated from the blood of CMV seropositive healthy donors by negative magnetic separation. Isolated NK cells were cultured in the presence of CMV lysate and analyzed for the expression of NKG2A, NKG2C, and CD57 by FACS caliber. The results showed that NKG2C expression is significantly upregulated in the presence of CMV lysate compared to without stimulated group (mean increase, 6.65 %; 95% CI, 0.2582 to 13.02; p=0.043; R square: 0.38). Likewise, results have shown a significant decrease in the frequency of NKG2A+CD57- NK cell subsets (p=0.005; 95% CI, -13.49 to -3.151; R square: 0.5957) in the stimulated group compared to without stimulated ones. According to these results, CMV may drive a direct influence on NK cell receptor repertoire, including the expansion of NK cells expressing NKG2C receptor, which is needed for further studies.

scholarly journals The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3285
Author(s):  
Linda Quatrini ◽  
Francesca Romana Mariotti ◽  
Enrico Munari ◽  
Nicola Tumino ◽  
Paola Vacca ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Tumour Response ◽  
Human Leukocyte ◽  
Surface Expression ◽  
Leukocyte Antigen ◽  
Inhibitory Function ◽  
Current Therapies ◽  
And Function

In the last years, immunotherapy with antibodies against programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has shown remarkable efficacy in the treatment of different types of tumours, representing a true revolution in oncology. While its efficacy has initially been attributed only to unleashing T cell responses, responsivity to PD-1/PD-L1 blockade was observed in some tumours with low Human Leukocyte Antigen (HLA) I expression and increasing evidence has revealed PD-1 surface expression and inhibitory function also in natural killer (NK) cells. Thus, the contribution of anti-PD-1/PD-L1 therapy to the recovery of NK cell anti-tumour response has recently been appreciated. Here, we summarize the studies investigating PD-1 expression and function in NK cells, together with the limitations and perspectives of immunotherapies. A better understanding of checkpoint biology is needed to design next-generation therapeutic strategies and to improve the clinical protocols of current therapies.

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